N-cyclopentyl modulators of chemokine receptor activity

ABSTRACT

The present invention is directed to compounds of the formula I:  
                 
 
     (wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, n, x and y are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CC R-3.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/138,886, filed Jun. 11, 1999, the disclosure of whichis hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Chemokines are chemotactic cytokines that are released by a widevariety of cells to attract macrophages, T cells, eosinophils, basophilsand neutrophils to sites of inflammation (reviewed in Schall, Cytokine,3, 165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). Thereare two classes of chemokines, C—X—C (α) and C—C (β), depending onwhether the first two cysteines are separated by a single amino acid(C—X—C) or are adjacent (C—C). The α-chemokines, such as interleukin-8(IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growthstimulatory activity protein (MGSA) are chemotactic primarily forneutrophils, whereas β-chemokines, such as RANTES, MIP-1α, MIP-1β,monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin arechemotactic for macrophages, T-cells, eosinophils and basophils (Deng,et al., Nature, 381, 661-666 (1996)).

[0003] The chemokines bind specific cell-surface receptors belonging tothe family of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal though theassociated trimeric G protein, resulting in a rapid increase inintracellular calcium concentration. There are at least sixteen humanchemokine receptors that bind or respond to Aβ-chemokines with thefollowing characteristic pattern: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1α, MIP-1β, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.,270, 22123-22128 (1995); Beote, et al, Cell, 72, 415-425 (1993)); CCR-2Aand CCR-2B (or “CKR-2A”/“CKR-2A” or “CC-CKR-2A”/“CC-CKR-2A”) [MCP-1,MCP-3, MCP-4]; CCR-3 (or “CKR-3” or “CC-CKR-3”) [eotaxin, RANTES, MCP-3](Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995); CCR-4 (or“CKR-4” or “CC-CKR4”) [MIP-1α, RANTES, MCP-1] (Power, et al., J. Biol.Chem., 270, 19495-19500 (1995)); CCR-5 (or “CKR-5” or “CC-CKR-5”)[MIP-1α, RANTES, MIP-1β] (Sanson, et al., Biochemistry, 35, 3362-3367(1996)); and the Duffy blood-group antigen [RANTES, MCP-1] (Chaudhun, etal., J. Biol. Chem., 269, 7835-7838 (1994)). The β-chemokines includeeotaxin, MIP (“macrophage inflammatory proteins), MCP (“monocytechemoattractant protein”) and RANTES (“regulation-upon-activation,normal T expressed and secreted”).

[0004] Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3,CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being importantmediators of inflammatory and immunoregulatory disorders and diseases,including asthma, rhinitis and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. A reviewof the role of chemokines in allergic inflammation is provided by Kita,H., et al., J. Exp. Med. 183, 2421-2426 (1996). Accordingly, agentswhich modulate chemokine receptors would be useful in such disorders anddiseases. Compounds which modulate chemokine receptors would beespecially useful in the treatment and prevention of atopic conditionsincluding allergic rhinitis, dermatitis, conjunctivitis, andparticularly bronchial asthma.

[0005] A retrovirus designated human immunodeficiency virus (HV-1) isthe etiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.This virus was previously known as LAV, HTLV-III, or ARV.

[0006] Certain compounds have been demonstrated to inhibit thereplication of HIV, including soluble CD4 protein and syntheticderivatives (Smith, et al., Science, 238, 1704-1707 (1987)), dextransulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes(U.S. Pat. No. 5,468,469). Some of these antiviral agents have beenshown to act by blocking the binding of gpl2O, the coat protein of HIV,to its target, the CD4 glycoprotein of the cell.

[0007] Entry of HIV-1 into a target cell requires cell-surface CD4 andadditional host cell cofactors. Fusin has been identified as a cofactorrequired for infection with virus adapted for growth in transformedT-cells, however, fusin does not promote entry of macrophagetropicviruses which are believed to be the key pathogenic strains of HIV invivo. It has recently been recognized that for efficient entry intotarget cells, human immunodeficiency viruses require a chemokinereceptors, most probably CCR-5 or CXCR-4, as well as the primaryreceptor CD4 (Levy, N. Engl. J. Med., 335(20), 1528-1530 (Nov. 14,1996). The principal cofactor for entry mediated by the envelopeglycoproteins of primary macrophage-trophic strains of mV-1 is CCR5, areceptor for the β-chemokines RANTES, MIP-1α and MIP-1β (Deng, et al.,Nature, 381, 661-666 (1996)). HIV attaches to the CD4 molecule on cellsthrough a region of its envelope protein, gp120, It is believed that theCD-4 binding site on the gp120 of HIV interacts with the CD4 molecule onthe cell surface, and undergoes conformational changes which allow it tobind to another cell-surface receptor, such as CCR5 and/or CXCR-4. Thisbrings the viral envelope closer to the cell surface and allowsinteraction between gp4l on the viral envelope and a fusion domain onthe cell surface, fusion with the cell membrane, and entry of the viralcore into the cell. It has been shown that β-chemokine ligands preventHIV-1 from fusing with the cell (Dragic, et al., Nature, 381, 667-673(1996)). It has further been demonstrated that a complex of gp120 andsoluble CD4 interacts specifically with CCR-5 and inhibits the bindingof the natural CCR-5 ligands MIP-1α and MIP-1β (Wu, et al., Nature, 384,179-183 (1996); Trkola, et al., Nature, 384, 184-187 (1996)).

[0008] Humans who are homozygous for mutant CCR-5 receptors which do notserve as co-receptors for HIV-1 in vitro appear to be unusuallyresistant to mV-1 infection and are not immuno-compromised by thepresence of this genetic variant (Nature, 382, 722-725 (1996)). Absenceof CCR-5 appears to confer substantial protection from mV-1 infection(Nature, 382, 668-669 (1996)). Other chemokine receptors may be used bysome strains of HIV-1 or may be favored by non-sexual routes oftransmission. Although most HIV-1 isolates studied to date utilize CCR-5or fusin, some can use both as well as the related CCR-2B and CCR-3 asco-receptors (Nature Medicine, 2(11), 1240-1243 (1996)). Nevertheless,drugs targeting chemokine receptors may not be unduly compromised by thegenetic diversity of HIV-1 (Zhang, et al., Nature, 383, 768 (1996)).Accordingly, an agent which could block chemokine receptors in humanswho possess normal chemokine receptors should prevent infection inhealthy individuals and slow or halt viral progression in infectedpatients. By focusing on the host's cellular immune response to HIVinfection, better therapies towards all subtypes of HIV may be provided.These results indicate that inhibition of chemokine receptors presents aviable method for the prevention or treatment of infection by HIV andthe prevention or treatment of AIDS.

[0009] The peptides eotaxin, RANTES, MIP-1α, MIP-1β, MCP-1, and MCP-3are known to bind to chemokine receptors. As noted above, the inhibitorsof HIV-1 replication present in supernatants of CD8+ T cells have beencharacterized as the β-chemokines RANTES, MIP-1α and MIP-1β.

SUMMARY OF THE INVENTION

[0010] The present invention is directed to compounds which inhibit theentry of human immunodeficiency virus (HIV) into target cells and are ofvalue in the prevention of infection by HIV, the treatment of infectionby HIV and the prevention and/or treatment of the resulting acquiredimmune deficiency syndrome (AIDS). The present invention also relates topharmaceutical compositions containing the compounds and to a method ofuse of the present compounds and other agents for the prevention andtreatment of AIDS and viral infection by HIV.

[0011] The present invention is further directed to compounds which aremodulators of chemokine receptor activity and are useful in theprevention or treatment of certain inflammatory and immunoregulatorydisorders and diseases, allergic diseases, atopic conditions includingallergic rhinitis, dermatitis, conjunctivitis, and asthma, as well asautoimmune pathologies such as rheumatoid arthritis and atherosclerosis.The invention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which chemokine receptorsare involved.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention is directed to compounds of formula I:

[0013] wherein:

[0014] X is selected from:

[0015] —(C₀₋₆ alkyl)—Y—(C₀₋₆ alkyl)—,

[0016] —(C₀₋₆ alkyl)—C₃₋₈ cycloalkyl-(C₀₋₆ alkyl)—,

[0017] C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl,

[0018] where the alkyl is unsubstituted or substituted with 1-7substituents where the substituents are independently selected from:

[0019] (a) halo,

[0020] (b) hydroxy,

[0021] (c) —O—C₁₋₃ alkyl, and

[0022] (d) trifluoromethyl,

[0023] and where Y is selected from:

[0024] a single bond, —O—, —SO₂—, —NR¹⁰—, —NR¹⁰—SO₂—, —SO₂—NR¹⁰—, —S—,and —SO—,

[0025] and where R¹⁰ is independently selected from: hydrogen, C₁₋₆alkyl, benzyl, phenyl, and C₁₋₆ alkyl-C₃₋₆ cycloalkyl,

[0026] which is unsubstituted or substituted with 1-3 substituents wherethe substituents are independently selected from: halo, C₁₋₃ alkyl, C₁₋₃alkoxy and trifluoromethyl;

[0027] R¹ is selected from:

[0028] (1) —CO₂H,

[0029] (2) —NO₂,

[0030] (3) -tetrazolyl,

[0031] (4) -hydroxyisoxazole,

[0032] (5) —SO₂NHCO—(C₀₋₃ alkyl)—R⁹, wherein R⁹ is independentlyselected from: hydrogen, C₁₋₆ alkyl, C₅₋₆ cycloalkyl, benzyl or phenyl,which is unsubstituted or substituted with 1-3 substituents where thesubstituents are independently selected from: halo, C₁₋₃ alkyl, C₁₋₃alkoxy and trifluoromethyl, and

[0033] (6) —P(O)(OH)₂;

[0034] R³ is selected from the group consisting of:

[0035] phenyl and heterocycle,

[0036] which is unsubstituted or substituted with 1-7 substituents wherethe substituents are independently selected from:

[0037] (a) halo,

[0038] (b) trifluoromethyl,

[0039] (c) hydroxy,

[0040] (d) C₁₋₃ alkyl,

[0041] (e) —O—C₁₋₃ alkyl,

[0042] (f) —CO₂R⁹,

[0043] (g) —NR⁹R¹⁰, and

[0044] (h) —CONR⁹R¹⁰;

[0045] R⁴, R⁵ and R⁶ are independently selected from:

[0046] hydrogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₂₋₁₀ alkenyl,

[0047] C₂₋₁₀ alkynyl, phenyl, —(C₁₋₆ alkyl)-phenyl,

[0048] —(C₁₋₆ alkyl)—C₃₋₈ cycloalkyl, naphthyl, biphenyl, andheterocycle,

[0049] which is unsubstituted or substituted with 1-7 of R¹¹ where R¹¹is independently selected from:

[0050] (a) halo,

[0051] (b) trifluoromethyl,

[0052] (c) hydroxy,

[0053] (d) C₁₋₃ alkyl,

[0054] (e) —O—C₁₋₃ alkyl,

[0055] (f) —CO₂R⁹,

[0056] (g) —NR⁹R¹⁰, and

[0057] (h) —CONR⁹R¹⁰,

[0058] or where R⁴ and R⁵ may be joined together to form a 3-8 memberedsaturated ring which may be unsubstituted or substituted with 1-7 ofR¹¹,

[0059] or where R⁵ and R⁶ may be joined together to form a 3-8 memberedsaturated ring which may be unsubstituted or substituted with 1-7 ofR¹¹;

[0060] R⁷ is selected from:

[0061] (1) hydrogen,

[0062] (2) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-4substituents where the substituents are independently selected from:hydroxy, cyano, and halo,

[0063] (3) hydroxy, and

[0064] (4) halo;

[0065] R⁸ is selected from:

[0066] hydrogen, C₃₋₈ cycloalkyl, phenyl, naphthyl, biphenyl, andheterocycle,

[0067] which is unsubstituted or substituted with 1-7 of R¹² where R¹²is independently selected from:

[0068] (a) halo,

[0069] (b) cyano,

[0070] (c) hydroxy,

[0071] (d) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5 ofR¹³ where R¹³ is independently selected from: halo, cyano, hydroxy, C₁₋₆alkoxy, —CO₂H, —CO₂(C₁₋₆ alkyl), trifluoromethyl, and —NR⁹R¹⁰,

[0072] (e) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5of R¹³,

[0073] (f) —CF₃,

[0074] (g) —CHF₂,

[0075] (h) —CH₂F,

[0076] (i) —NO₂,

[0077] (j) C₀₋₆ alkyl-phenyl or C₀₋₆ alkyl-heterocycle, which isunsubstituted or substituted with 1-7 substituents where thesubstituents are independently selected from:

[0078] (i) halo,

[0079] (ii) hydroxy,

[0080] (iii) C₁₋₆ alkyl, unsubstituted or substituted with 1-5substituents, each of which is independently selected from halo, cyano,hydroxy, C₁₋₆ alkoxy, —CO₂H, —CO₂(C₁₋₆ alkyl), trifluoromethyl, and—NR⁹R¹⁰,

[0081] (iv) —O—C₁₋₆ alkyl,

[0082] (v) —CF₃,

[0083] (vi) —OCF₃,

[0084] (vii) —NO₂,

[0085] (viii) —CN,

[0086] (ix) —SO₂—C₁₋₆ alkyl,

[0087] (x) —CO₂R⁹,

[0088] (xi) —NR⁹R¹⁰,

[0089] (xii) —CONR⁹R¹⁰,

[0090] (xiii) —SO₂—NR⁹R¹⁰,

[0091] (xiv) —NR₉—SO₂—R¹⁰,

[0092] (xv) —C₃₋₈ cycloalkyl,

[0093] (xvi) —OC₃₋₈ cycloalkyl, and

[0094] (xvii) phenyl;

[0095] (k) —CO₂R⁹,

[0096] (l) tetrazolyl,

[0097] (m) —NR⁹R¹⁰,

[0098] (n) —NR⁹—COR¹⁰,

[0099] (o) —NR⁹—CO₂R¹⁰,

[0100] (p) —CO—NR⁹R¹⁰,

[0101] (q) —OCO—NR⁹R¹⁰,

[0102] (r) —NR⁹CO—NR⁹R¹⁰,

[0103] (s) —S(O)_(m)—R⁹,wherein m is an integer selected from 0, 1 and2,

[0104] (t) —S(O)₂—NR⁹R¹⁰,

[0105] (u) —NR⁹S(O)₂—R¹⁰,

[0106] (v) —NR⁹S(O)₂—NR⁹R¹⁰,

[0107] (w) C₁₋₆ alkyl substituted with —C₃₋₈ cycloalkyl, and

[0108] (x) —C₃₋₈ cycloalkyl;

[0109] n is an integer selected from 1, 2, 3 and 4;

[0110] x is an integer selected from 0, 1 and 2, and y is an integerselected from 0, 1 and 2, with the proviso that the sum of x and y is 2;

[0111] and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

[0112] In one embodiment, the present invention is directed to compoundsof Formula I, and pharmaceutically acceptable salts thereof andindividual diastereomers thereof, wherein

[0113] R¹ is selected from:

[0114] (1) —CO₂H,

[0115] (2) —NO₂,

[0116] (3) -tetrazolyl,

[0117] (4) -hydroxyisoxazole, and

[0118] (5) —P(O)(OH)₂;

[0119] R⁸ is selected from:

[0120] hydrogen, C₃₋₈ cycloalkyl, phenyl, naphthyl, biphenyl, andheterocycle,

[0121] which is unsubstituted or substituted with 1-7 of R¹² where R¹²is independently selected from:

[0122] (a) halo,

[0123] (b) cyano,

[0124] (c) hydroxy,

[0125] (d) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5 ofR¹³ where R¹³ is independently selected from: halo, cyano, hydroxy, C₁₋₆alkoxy, —CO₂H, —CO₂(C₁₋₆ alkyl), trifluoromethyl, and —NR⁹R¹⁰,

[0126] (e) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5of R¹³,

[0127] (f) —CF₃,

[0128] (g) —CHF₂,

[0129] (h) —CH₂F,

[0130] (i) —NO₂,

[0131] (j) C₀₋₆ alkyl-phenyl or C₀₋₆ alkyl-heterocycle, which isunsubstituted or substituted with 1-7 substituents where thesubstituents are independently selected from:

[0132] (i) halo,

[0133] (ii) hydroxy,

[0134] (iii) C₁₋₆ alkyl,

[0135] (iv) —O—C₁₋₆ alkyl,

[0136] (v) —CF₃,

[0137] (vi) —OCF₃,

[0138] (vii) —NO₂,

[0139] (viii) —CN,

[0140] (ix) —SO₂—C₁₋₆ alkyl,

[0141] (x) —CO₂R⁹,

[0142] (xi) —NR⁹R¹⁰,

[0143] (xii) —CONR⁹R¹⁰,

[0144] (xiii) —SO₂—NR⁹R¹⁰, and

[0145] (xiv) —NR⁹—SO₂—R¹⁰;

[0146] (k) —CO₂R⁹,

[0147] (l) tetrazolyl,

[0148] (m) —NR⁹R¹⁰,

[0149] (n) —NR⁹—COR¹⁰,

[0150] (o) —NR⁹—CO₂R¹⁰,

[0151] (p) —CO—NR⁹R¹⁰,

[0152] (q) —OCO—NR⁹R¹⁰,

[0153] (r) —NR⁹CO—NR⁹R¹⁰,

[0154] (s) —S(O)_(m)—R⁹,wherein m is an integer selected from 0, 1 and2,

[0155] (t) —S(O)₂—NR⁹R¹⁰,

[0156] (u) —NR⁹S(O)₂—R¹⁰, and

[0157] (v) —NR⁹S(O)₂—NR⁹R¹⁰;

[0158] and all else is as defined above.

[0159] Preferred compounds of the present invention include those offormula Ia:

[0160] wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, X and n are defined herein;

[0161] and pharmaceutically acceptable salts and individualdiastereomers thereof.

[0162] More preferred compounds of the present invention include thoseof formula Ic:

[0163] wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸ and X are defined herein;

[0164] and pharmaceutically acceptable salts and individualdiastereomers thereof.

[0165] Highly preferred compounds of the present invention include thoseof formula Id:

[0166] wherein R³, R⁴, R⁵, R⁶, R⁸ and X are defined herein;

[0167] and pharmaceutically acceptable salts and individualdiastereomers thereof.

[0168] More highly preferred compounds of the present invention includethose of formula Ie:

[0169] wherein R⁴, R⁵, R⁶, R⁸ and X are defined herein;

[0170] and pharmaceutically acceptable salts and individualdiastereomers thereof.

[0171] In the present invention it is preferred that R¹ is selectedfrom:

[0172] (1) —CO₂H,

[0173] (2) —P(O)(OH)₂, and

[0174] (3) -tetrazolyl.

[0175] In the present invention it is more preferred that R¹ is selectedfrom:

[0176] (1) —CO₂H, and

[0177] (2) -tetrazolyl.

[0178] In the present invention it is even more preferred that R¹ is—CO₂H.

[0179] In the present invention it is preferred that R³ is selected fromthe group consisting of:

[0180] phenyl and thienyl,

[0181] which may be unsubstituted or substituted with 1-5 substituentswhere the substituents are independently selected from:

[0182] (a) halo,

[0183] (b) trifluoromethyl,

[0184] (c) hydroxy,

[0185] (d) C₁₋₃ alkyl, and

[0186] (e) —O—C₁₋₃ alkyl.

[0187] In the present invention it is more preferred that R³ is selectedfrom the group consisting of:

[0188] phenyl and thienyl,

[0189] which may be unsubstituted or substituted with 1-5 substituentswhere the substituents are independently selected from:

[0190] (a) fluoro,

[0191] (b) chloro,

[0192] (c) trifluoromethyl,

[0193] (d) hydroxy, and

[0194] (e) C₁₋₃ alkyl.

[0195] In the present invention it is even more preferred that R³ isselected from the group consisting of:

[0196] phenyl, which may be unsubstituted or substituted with 1-5substituents where the substituents are independently selected from:

[0197] (a) fluoro, and

[0198] (b) chloro; and

[0199] unsubstituted thienyl.

[0200] In the present invention it is still more preferred that R³ isunsubstituted phenyl, (3-fluoro)phenyl or 3-thienyl.

[0201] In the present invention it is preferred that R⁴ is hydrogen orC₁₋₆ alkyl.

[0202] In the present invention it is more preferred that R⁴ ishydrogen.

[0203] In the present invention it is preferred that R⁵ is selectedfrom: hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyl-C₃₋₈ cycloalkyl,and phenyl.

[0204] In the present invention it is more preferred that R⁵ is selectedfrom: hydrogen, methyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, —CH₂-cyclopropyl, —CH₂-cyclobutyl, and phenyl.

[0205] In the present invention it is still more preferred that R⁵ isselected from: isopropyl, isobutyl, sec-butyl, and cyclohexyl.

[0206] In the present invention it is preferred that R⁶ is selectedfrom: hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyl-C₃₋₈ cycloalkyl,and phenyl.

[0207] In the present invention it is more preferred that R⁶ is selectedfrom: hydrogen, methyl, n-butyl, t-butyl, isobutyl, sec-butyl,—CH₂-cyclopropyl, —CH₂-cyclobutyl, and cyclohexyl.

[0208] In the present invention it is still more preferred that R⁶ isselected from: hydrogen, methyl, —CH₂-cyclopropyl, —CH₂-cyclobutyl, andcyclohexyl.

[0209] In an alternate embodiment of the present invention it ispreferred that R⁵ and R⁶ are joined together to form a C₃₋₈ cycloalkylring.

[0210] In an alternate embodiment of the present invention it is morepreferred that R⁵ and R⁶ are joined together to form a pyrrolidine ring.

[0211] In another alternate embodiment of the present invention it ismore preferred that R⁴ and R⁵ are joined together to form a C₃₋₈cycloalkyl ring. In an aspect of this embodiment, the ring formed byjoining R⁴ and R⁵ is cyclopentyl.

[0212] In the present invention it is preferred that R⁷ is hydrogen,fluoro, hydroxy or C₁₋₆ alkyl.

[0213] In the present invention it is more preferred that R⁷ is hydrogenor fluoro.

[0214] In the present invention it is even more preferred that R⁷ ishydrogen.

[0215] In the present invention it is preferred that X is:

[0216] —(C₀₋₄ alkyl)—Y—(C₀₋₄ alkyl)—,

[0217] where the alkyl is unsubstituted or substituted with 1-4substituents where the substituents are independently selected from:

[0218] (a) halo,

[0219] (b) hydroxy,

[0220] (c) —O—C₁₋₃ alkyl, and

[0221] (d) trifluoromethyl,

[0222] and where Y is selected from:

[0223] a single bond, —O—, —SO₂—,

[0224] NR¹⁰—, —S—, and —SO—,

[0225] and where R¹⁰ is independently selected from: hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, benzyl, phenyl, and C₁₋₆ alkyl-C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-3 substituentswhere the substituents are independently selected from: halo, C₁₋₃alkyl, C₁₋₃ alkoxy and trifluoromethyl.

[0226] In the present invention it is more preferred that X is:

[0227] —(C₀₋₂ alkyl)—Y—(C₀₋₂ alkyl)—,

[0228] where the alkyl is unsubstituted or substituted with 1-4substituents where the substituents are independently selected from:

[0229] (a) halo,

[0230] (b) hydroxy,

[0231] (c) —O—C₁₋₃ alkyl, and

[0232] (d) trifluoromethyl,

[0233] and where Y is selected from:

[0234] a single bond, —O—, —SO₂—, —NR¹⁰—, —S—, and —SO—,

[0235] where R¹⁰ is independently selected from: hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, benzyl, phenyl, and C₁₋₆ alkyl-C₃₋₆cycloalkyl,

[0236] which is unsubstituted or substituted with 1-3 substituents wherethe substituents are independently selected from: halo, C₁₋₃ alkyl,

[0237] C₁₋₃ alkoxy and trifluoromethyl.

[0238] In the present invention it is even more preferred that X isselected from:

[0239] —(C₀₋₂ alkyl)—Y—(C₀₋₂ alkyl)—, where the alkyl is unsubstitutedor substituted with fluoro,

[0240] and where Y is selected from:

[0241] a single bond, —SO₂—, —SO—, and —NR¹⁰—,

[0242] where R¹⁰ is independently selected from: hydrogen, C₁₋₃ alkyl,C₂₋₃ alkenyl, and C₂₋₃ alkynyl.

[0243] In the present invention it is still more preferred that X isselected from:

[0244] (1) a single bond,

[0245] (2) —CH₂CH₂—,

[0246] (3) —CH₂CH₂CH₂—,

[0247] (4) —CH₂CH₂—CF₂—,

[0248] (5) —CH₂CH₂—SO₂—, and

[0249] (6) —CH₂CH₂—SO—.

[0250] In the present invention it is preferred that R⁸ is selectedfrom: phenyl, naphthyl, cyclohexyl, benzoimidazolyl, benzofurazanyl,imidazopyridyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl,pyridazinyl, pyridyl, pyrimidyl, thiazolyl, tetrazolopyridyl, pyrazolyl,tetrahydroindazolyl, tetrahydroimidazopyridyl, andtetrahydropyrazolopyridyl;

[0251] which is unsubstituted or substituted with 1-7 substituents wherethe substituents are independently selected from:

[0252] (a) halo,

[0253] (b) cyano,

[0254] (c) hydroxy,

[0255] (d) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5 ofR¹³ where R¹³ is independently selected from: halo, cyano, hydroxy, C₁₋₆alkoxy, —CO₂H, —CO₂(C₁₋₆ alkyl), trifluoromethyl, and —NR⁹R¹⁰, whereinR⁹ and R¹⁰ are independently selected from: hydrogen, C₁₋₆ alkyl, C₅₋₆cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with1-3 substituents where the substituents are independently selected from:halo, C₁₋₃ alkyl, C₁₋₃ alkoxy and trifluoromethyl;

[0256] (e) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5of R¹³,

[0257] (f) —CF₃,

[0258] (g) —CHF₂,

[0259] (h) —CH₂F,

[0260] (i) —NO₂,

[0261] (j) C₀₋₆ alkyl-phenyl or C₀₋₆ alkyl-heterocycle, which isunsubstituted or substituted with 1-7 substituents where thesubstituents are independently selected from:

[0262] (i) halo,

[0263] (ii) hydroxy,

[0264] (iii) C₁₋₆ alkyl,

[0265] (iv) —O—C₁₋₆ alkyl,

[0266] (v) —CF₃,

[0267] (vi) —OCF₃,

[0268] (vii) —NO₂,

[0269] (viii) —CN,

[0270] (ix) —SO₂—C₁₋₆ alkyl,

[0271] (x) —CO₂R⁹,

[0272] (xi) —NR⁹R¹⁰,

[0273] (xii) —CONR⁹R¹⁰,

[0274] (xiii) —SO₂—NR⁹R¹⁰, and

[0275] (xiv) —NR⁹—SO₂—R¹⁰;

[0276] (k) —CO₂R⁹,

[0277] (l) tetrazolyl,

[0278] (m) —NR⁹R¹⁰,

[0279] (n) —NR⁹—COR¹⁰,

[0280] (o) —NR⁹—CO₂R¹⁰,

[0281] (p) —CO—NR⁹R¹⁰,

[0282] (q) —OCO—NR⁹R¹⁰,

[0283] (r) —NR⁹CO—NR⁹R¹⁰,

[0284] (s) —S(O)_(m)—R⁹,wherein m is an integer selected from 0, 1 and

[0285] (t) —S(O)₂—NR⁹R¹⁰,

[0286] (u) —NR⁹S(O)₂—R¹⁰, and

[0287] (v) —NR₉S(O)₂—NR⁹R¹⁰.

[0288] In an aspect of the preceding embodiment, in the presentinvention it is preferred that R⁸ is selected from: phenyl, naphthyl,cyclohexyl, benzoimidazolyl, benzofurazanyl, imidazopyridyl, imidazolyl,isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl,thiazolyl, and tetrazolopyridyl; which is unsubstituted or substitutedwith 1-7 substituents as set forth in the preceding paragraph.

[0289] In the present invention it is more preferred that R⁸ is selectedfrom: phenyl, imidazopyridyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl,thiazolyl, tetrahydroindazolyl, tetrahydroimidazopyridyl, andtetrahydropyrazolopyridyl;

[0290] which is unsubstituted or substituted with 1-5 substituents wherethe substituents are independently selected from:

[0291] (a) halo,

[0292] (b) cyano,

[0293] (c) —NO₂,

[0294] (d) —CF₃,

[0295] (e) —CHF₂,

[0296] (f) —CH₂F,

[0297] (h) C₁₋₆ alkyl,

[0298] (i) C₁₋₃ alkyl-phenyl or C₁₋₃ alkyl-pyridyl, which isunsubstituted or substituted with 1-4 substituents where thesubstituents are independently selected from:

[0299] (i) halo,

[0300] (ii) C₁₋₆ alkyl,

[0301] (iii) —O—C₁₋₆ alkyl,

[0302] (iv) —CF₃,

[0303] (vi) —OCF₃,

[0304] (vii) —CN, and

[0305] (j) —O—C₁₋₆ alkyl.

[0306] In an aspect of the preceding embodiment, in the presentinvention it is preferred that R⁸ is selected from: phenyl,imidazopyridyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, and thiazolyl;which is unsubstituted or substituted with 1-5 substituents as set forthin the preceding paragraph.

[0307] In the present invention it is even more preferred that R⁸ isselected from: imidazolyl, oxazolyl, pyrazolyl, thiazolyl,tetrahydroindazolyl, tetrahydroimidazopyridyl, andtetrahydropyrazolopyridyl; which is unsubstituted or substituted with1-3 substituents where the substituents are independently selected from:

[0308] (a) fluoro,

[0309] (b) cyano,

[0310] (c) C₁₋₃ alkyl,

[0311] (d) —CH₂-phenyl, which is unsubstituted or substituted with 1-4substituents where the substituents are independently selected from:

[0312] (i) fluoro,

[0313] (ii) chloro,

[0314] (iii) —O—CH₃,

[0315] (iv) —CF₃,

[0316] (v) —CN, and

[0317] (e) —CF₃.

[0318] In an aspect of the preceding embodiment, in the presentinvention it is preferred that R⁸ is selected from: imidazolyl,oxazolyl, pyrazolyl, and thiazolyl; which is unsubstituted orsubstituted with 1-3 substituents as set forth in the precedingparagraph.

[0319] In the present invention it is still more preferred that R⁸ isselected from: 5-(3-benzyl)pyrazolyl, 5-(1-methyl-3-benzyl)pyrazolyl,5-(1-ethyl-3-benzyl)pyrazolyl, 5-(2-benzyl)thiazolyl,5-(2-benzyl-4-methyl)thiazolyl, and 5-(2-benzyl4-ethyl)thiazolyl).

[0320] In the present invention it is preferred that n is an integerselected from 1, 2 and 3.

[0321] In the present invention it is more preferred that n is aninteger which is 1.

[0322] In the present invention it is preferred that x is an integerwhich is 1 and y is an integer which is 1.

[0323] It is to be understood that embodiments of the present inventioninclude, but are not limited to, compounds of formula I wherein R¹, R³,R⁴, R⁵, R⁶, R⁷, R⁸, x, y and n are defined in accordance with one of theembodiments or aspects thereof as set forth above. Any and all possiblecombinations of preferred, more preferred, even more preferred, highlypreferred, more highly preferred, and most preferred definitions ofthese variables in formulas I are within the scope of the presentinvention.

[0324] The compounds of the instant invention have at least twoasymmetric centers at the ring junction of the substitutents bearing thepiperidine and R³. Additional asymmetric centers may be presentdepending upon the nature of the various substituents on the molecule.Each such asymmetric center will independently produce two opticalisomers and it is intended that all of the possible optical isomers anddiastereomers in mixtures and as pure or partially purified compoundsare included within the ambit of this invention. The relativeconfigurations of the more preferred compounds of this invention are ofthe trans orientation, i.e. as depicted:

[0325] The relative configurations of the even more preferred compoundsof this invention wherein R⁶ is hydrogen, methyl or wherein R⁵ and R⁶form a pyrrolidine ring with respect to the configuration of thenitrogen substituent on the cyclopentane ring is cis to the orientationof R³ as depicted:

[0326] The relative configurations of the most preferred compounds ofthis invention wherein R⁶ is hydrogen or methyl with respect to theconfiguration of the nitrogen substituent on the cyclopentane ring is iscis to the orientation of R³ and with the (R)-stereochemistry of thenitrogen side chain of the orientation as depicted:

[0327] The relative configurations of the even more preferred compoundsof this invention wherein R⁶ is other than hydrogen or methyl withrespect to the configuration of the nitrogen substituent on thecyclopentane ring is 1,3-cis of the orientation as depicted:

[0328] The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

[0329] In a preferred aspect the present invention is a compound offormula (II);

[0330] wherein

[0331] R⁴ is

[0332] R⁸ is selected from the group consisting of

[0333] R¹² and R¹⁴ are each independently selected from the groupconsisting of F, Cl, CF₃, OCH₃, OCH₂CH₃, OCF₃, O-cyclobutyl, CN,O-cyclopropyl, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, and SO₂CH₃;

[0334] G is hydrogen or fluoro; and

[0335] q is an integer equal to 1 or 2;

[0336] and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

[0337] As appreciated by those of skill in the art, halo or halogen asused herein are intended to include chloro, fluoro, bromo and iodo.Similarly, C_(1-8,) as in C₁₋₈ alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branchedarrangement, such that C₁₋₈ alkyl specifically includes methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl and octyl. Likewise, C₀, as in C₀alkyl is defined to identify the presence of a direct covalent bond.

[0338] The term “heterocycle” (which may alternatively be referred to as“heterocyclic”) refers to a 4- to 8-membered monocyclic ring, a 7- to11-membered bicyclic system, or a 10 to 15-membered tricyclic ringsystem, any ring of which is saturated or unsaturated (partially ortotally), and which consists of carbon atoms and one or more heteroatoms(e.g., from 1 to 4 heteroatoms) selected from N, O and S, and whereinthe nitrogen and sulfur heteroatoms may optionally be oxidized, thenitrogen heteroatom may optionally be quaternized, and a ring carbon mayoptionally be oxidized (i.e., is substituted with oxo). The heterocyclicring may be attached at any heteroatom or carbon atom, provided thatattachment results in the creation of a stable structure. A preferredheterocycle is a 4- to 8-membered monocyclic ring or a 7- to 11-memberedbicyclic system, as defined and described above.

[0339] The term “heterocycle” as used herein is intended to include thefollowing groups: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof.

[0340] The term “heterocycle” as used herein is also intended toinclude, but is not limited to, the following groups:methylenedioxyphenyl, imidazopyridyl, imidazopyrimidinyl,imidazopyridazinyl, imidazopyrazinyl, imidazotriazinyl,imidazothiopheyl, pyrazolopyridyl, pyrazolopyrimidinyl,pyrazolopyridazinyl, pyrazolopyrazinyl, pyrazolotriazinyl,pyrazolothiophenyl, triazolopyridyl, triazolopyrimidinyl,triazolopyridazinyl, triazolopyrazinyl, triazolothiophenyl,tetrahydroimidazopyridinyl, tetrahydropyrazolopyridinyl,tetrahydrotriazopyridinyl, tetrahydrotriazolopyridazinyl, andtetrahydroindazolyl.

[0341] The term “heterocycle” as used herein is also intended toinclude, but is not limited to, the following groups:tetrahydroimidazopyrimidyl, tetrahydroimidazopyrazinyl,tetrahydroimidazopyridazinyl, tetrahydrotriazolopyrimidyl,tetrahydrotriazolopyrazinyl, tetrahydropyrazolopyrimidyl,tetrahydropyrazolopyrazinyl, imidazothiazolyl, and imidazothiadiazolyl.

[0342] The term “heterocycle” as used herein is also intended toinclude, but is not limited to, oxopyridinyl (e.g., 2-oxopyridinyl),oxopiperidinyl, and oxopyrazolyl.

[0343] The terms “thiophenyl” and “thienyl” have the same meaning hereinand are used interchangeably. Similarly, the following pairs of termsare used interchangeably: “indazolyl” and “benzopyrazolyl”; “pyridinyl”and “pyridyl”.

[0344] In the expression “ . . . which is unsubstituted or substitutedwith . . . ”, “which” is intended to refer back to all precedingchemical groups in the particular definition in which the expressionappears, unless a contrary meaning is expressed or is implied by thecontext. Furthermore, the term “substituted” in the expression includesmono- and poly-substitution by a named substituent to the extent suchsingle and multiple substitution is chemically allowed in any of thenamed chemical groups. Thus, for example, the expression “isindependently selected from: hydrogen, C₁₋₆ alkyl, C₅₋₆ cycloalkyl,benzyl or phenyl, which is unsubstituted or substituted with 1-3substituents . . . ”, encompasses hydrogen, C₁₋₆ alkyl, C₅₋₆ cycloalkyl,benzyl, phenyl, mono- and di- and tri-substituted C₁₋₆ alkyl, mono- anddi- and tri-substituted C₅₋₆ cycloalkyl, mono- and di- andtri-substituted benzyl and mono- and di- and tri-substituted phenyl.

[0345] Exemplifying the invention is the use of the compounds disclosedin the Examples and herein.

[0346] Specific compounds within the present invention include acompound which is selected from the group consisting of:

[0347] and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

[0348] Specific compounds within the present invention also includecompounds selected from the group consisting of:

[0349] and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

[0350] An aspect of the present invention is a compound selected fromthe group consisting of:

[0351] and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

[0352] Another aspect of the present invention is

[0353] or a pharmaceutically acceptable salt thereof.

[0354] The subject compounds are useful in a method of modulatingchemokine receptor activity in a patient in need of such modulationcomprising the administration of an effective amount of the compound.

[0355] The present invention is directed to the use of the foregoingcompounds as modulators of chemokine receptor activity. In particular,these compounds are useful as modulators of the chemokine receptors,including CCR-5 and/or CCR3.

[0356] The utility of the compounds in accordance with the presentinvention as modulators of chemokine receptor activity may bedemonstrated by methodology known in the art, such as the assay forchemokine binding as disclosed by Van Riper, et al., J. Exp. Med 177851-856 (1993) which may be readily adapted for measurement of CCR-5binding, and the assay for CCR-3 binding as disclosed by Daugherty, etal., J. Exp. Med. 183, 2349-2354 (1996). Cell lines for expressing thereceptor of interest include those naturally expressing the receptor,such as EOL-3 or THP-1, or a cell engineered to express a recombinantreceptor, such as CHO, RBL-2H3, HEK-293. For example, a CCR3 transfectedAML14.3D10 cell line has been placed on restricted deposit with AmericanType Culture Collection in Rockville, Md. as ATCC No. CRL-12079, on Apr.5, 1996. The utility of the compounds in accordance with the presentinvention as inhibitors of the spread of HIV infection in cells may bedemonstrated by methodology known in the art, such as the HIVquantitation assay disclosed by Nunberg, et al., J. Virology, 65 (9),4887-4892 (1991).

[0357] In particular, the compounds of the following examples hadactivity in binding to the CCR-5 or the CCR-3 receptor in theaforementioned assays, generally with an IC₅₀ of less than about 1 μM.Such a result is indicative of the intrinsic activity of the compoundsin use as modulators of chemokine receptor activity.

[0358] Mammalian chemokine receptors provide a target for interferingwith or promoting eosinophil and/or lymphocyte function in a mammal,such as a human. Compounds which inhibit or promote chemokine receptorfunction, are particularly useful for modulating eosinophil and/orlymphocyte function for therapeutic purposes. Accordingly, the presentinvention is directed to compounds which are useful in the preventionand/or treatment of a wide variety of inflammatory and immunoregulatorydisorders and diseases, allergic diseases, atopic conditions includingallergic rhinitis, dermatitis, conjunctivitis, and asthma, as well asautoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

[0359] For example, an instant compound which inhibits one or morefunctions of a mammalian chemokine receptor (e.g., a human chemokinereceptor) may be administered to inhibit (i.e., reduce or prevent)inflammation. As a result, one or more inflammatory processes, such asleukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes,histamine) or inflammatory mediator release, is inhibited. For example,eosinophilic infiltration to inflammatory sites (e.g., in asthma) can beinhibited according to the present method.

[0360] Similarly, an instant compound which promotes one or morefunctions of a mammalian chemokine receptor (e.g., a human chemokine) isadministered to stimulate (induce or enhance) an inflammatory response,such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes,histamine) or inflammatory mediator release, resulting in the beneficialstimulation of inflammatory processes. For example, eosinophils can berecruited to combat parasitic infections.

[0361] In addition to primates, such as humans, a variety of othermammals can be treated according to the method of the present invention.For instance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

[0362] Diseases and conditions associated with inflammation andinfection can be treated using the method of the present invention. In apreferred embodiment, the disease or condition is one in which theactions of eosinophils and/or lymphocytes are to be inhibited orpromoted, in order to modulate the inflammatory response.

[0363] Diseases or conditions of humans or other species which can betreated with inhibitors of chemokine receptor function, include, but arenot limited to: inflammatory or allergic diseases and conditions,including respiratory allergic diseases such as asthma, particularlybronchial asthma, allergic rhinitis, hypersensitivity lung diseases,hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler'ssyndrome, chronic eosinophilic pneumonia), delayed-typehypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis.

[0364] Diseases or conditions of humans or other species which can betreated with promoters of chemokine receptor function, include, but arenot limited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS, individuals undergoingradiation therapy, chemotherapy, therapy for autoimmune disease or otherdrug therapy (e.g., corticosteroid therapy), which causesimmunosuppression; immunosuppression due congenital deficiency inreceptor function or other causes; and infectious diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworrns) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migrans (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larvamigrans (Ancylostona braziliense, Ancylostoma caninum).

[0365] The compounds of the present invention are accordingly useful inthe prevention and treatment of a wide variety of inflammatory andimmunoregulatory disorders and diseases, allergic conditions, atopicconditions, as well as autoimmune pathologies.

[0366] In another aspect, the instant invention may be used to evaluateputative specific agonists or antagonists of chemokine receptors,including CCR-5 and/or CCR-3. Accordingly, the present invention isdirected to the use of these compounds in the preparation and executionof screening assays for compounds which modulate the activity ofchemokine receptors. For example, the compounds of this invention areuseful for isolating receptor mutants, which are excellent screeningtools for more potent compounds. Furthermore, the compounds of thisinvention are useful in establishing or determining the binding site ofother compounds to chemokine receptors, e.g., by competitive inhibition.The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors,including CCR-5 and/or CCR-3. As appreciated in the art, thoroughevaluation of specific agonists and antagonists of the above chemokinereceptors has been hampered by the lack of availability of non-peptidyl(metabolically resistant) compounds with high binding affinity for thesereceptors. Thus the compounds of this invention are commercial productsto be sold for these purposes.

[0367] The present invention is further directed to a method for themanufacture of a medicament for modulating chemokine receptor activityin humans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

[0368] The present invention is further directed to the use of thesecompounds in the prevention or treatment of infection by a retrovirus,in particular, the human immunodeficiency virus (HIV) and the treatmentof, and delaying of the onset of consequent pathological conditions suchas AIDS. Treating AIDS or preventing or treating infection by HIV isdefined as including, but not limited to, treating a wide range ofstates of HIV infection: AIDS, ARC (AIDS related complex), bothsymptomatic and asymptomatic, and actual or potential exposure to HIV.For example, the compounds of this invention are useful in treatinginfection by HIV after suspected past exposure to HIV by, e.g., bloodtransfusion, organ transplant, exchange of body fluids, bites,accidental needle stick, or exposure to patient blood during surgery.

[0369] In a preferred aspect of the present invention, a subjectcompound may be used in a method of inhibiting the binding of achemokine to a chemokine receptor, such as CCR-5 or CCR-3, of a targetcell, which comprises contacting the target cell with an amount of thecompound which is effective at inhibiting the binding of the chemokineto the chemokine receptor.

[0370] The subject treated in the methods above is a mammal, preferablya human being, male or female, in whom modulation of chemokine receptoractivity is desired. “Modulation” as used herein is intended toencompass antagonism, agonism, partial antagonism, inverse agonismand/or partial agonism. In a preferred aspect of the present invention,modulation refers to antagonism of chemokine receptor activity. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

[0371] The term “composition” as used herein is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

[0372] The terms “administration of” and or “administering a” compoundshould be understood to mean providing a compound of the invention tothe individual in need of treatment.

[0373] Combined therapy to modulate chemokine receptor activity andthereby prevent and treat inflammatory and immunoregulatory disordersand diseases, including asthma and allergic diseases, as well asautoimmune pathologies such as rheumatoid arthritis and atherosclerosis,and those pathologies noted above is illustrated by the combination ofthe compounds of this invention and other compounds which are known forsuch utilities.

[0374] For example, in the treatment or prevention of inflammation, thepresent compounds may be used in conjunction with an antiinflammatory oranalgesic agent such as an opiate agonist, a lipoxygenase inhibitor,such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, suchas a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the instant compounds maybe administered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine. Likewise,compounds of the present invention may be used in combination with otherdrugs that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which compounds of thepressent invention are useful. Such other drugs may be administered, bya route and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention. Examples of otheractive ingredients that may be combined with a compound of the presentinvention, either administered separately or in the same pharmaceuticalcompositions, include, but are not limited to: (a) VLA-4 antagonistssuch as those described in U.S. Pat. No. 5,510,332, WO95/15973,WO96/01644, WO96/06108, WO96/20216, WO96/22966, WO96/31206, WO96/40781,WO97/03094, WO97/02289, WO 98/42656, WO98/53814, WO98/53817, WO98/53818,WO98/54207, and WO98/58902; (b) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus,rapamycin and other FK-506 type immunosuppressants; (d) antihistamines(H1-histamine antagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as β2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (i) other antagonists of thechemokine receptors, especially CXCR4, CCR-1, CCR-2, CCR-3 and CCR-5;(j) cholesterol lowering agents such as HMG-CoA reductase inhibitors(lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, andother statins), sequestrants (cholestyramine and colestipol), nicotinicacid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrateand benzafibrate), and probucol; (k) anti-diabetic agents such asinsulin, sulfonylureas, biguanides (metformin), α-glucosidase inhibitors(acarbose) and glitazones (troglitazone and pioglitazone); (1)preparations of interferon beta (interferon beta-1α, interferonbeta-1β); (m) other compounds such as 5-aminosalicylic acid and prodrugsthereof, antimetabolites such as azathioprine and 6-mercaptopurine, andcytotoxic cancer chemotherapeutic agents. The weight ratio of thecompound of the compound of the present invention to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the present invention is combined with anNSAID the weight ratio of the compound of the present invention to theNSAID will generally range from about 1000:1 to about 1:1000, preferablyabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

[0375] The present invention is further directed to combinations of thepresent compounds with one or more agents useful in the prevention ortreatment of AIDS. For example, the compounds of this invention may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of the AIDSantivirals, immunomodulators, anti-infectives, or vaccines known tothose of ordinary skill in the art. Drug Name Manufacturer IndicationANTIVIRALS 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleosidereverse transcriptase inhibitor) 141 W94 Glaxo Wellcome HIV infection,AIDS, ARC (protease inhibitor) 1592U89 Glaxo Wellcome HIV infection,AIDS, ARC Acemannan Carrington Labs ARC (Irving, TX) Acyclovir BurroughsWellcome HIV infection, AIDS, ARC, in combination with AZT AD-439 TanoxBiosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIVinfection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infectionAL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDS AlphaInterferon Glaxo Wellcome Kaposi's sarcoma, HIV in combinationw/Retrovir Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont(Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC neutralizespH Concepts labile alpha aberrant (Rockville, MD) Interferon AR177Aronex Pharm HIV infection, AIDS, ARC beta-fluoro-ddA Nat'l CancerInstitute AIDS-associated diseases (-)6-Chloro-4(S)- Merck HIVinfection, AIDS, cyclopropylethynyl- ARC 4(S)-trifluoro-methyl-(non-nucleoside 1,4-dihydro-2H-3,1- reverse transcriptasebenzoxazin-2-one inhibitor) CI-1012 Warner-Lambert HIV-1 infectionCidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlansulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMVretinitis immune globin Cytovene Syntex sight threatening CMVGanciclovir peripheral CMV retinitis Delaviridine Pharmacia-Upjohn HIVinfection, AIDS, ARC (protease inhibitor) Dextran Sulfate Ueno FineChem. Ind. AIDS, ARC, HIV Ltd. (Osaka, Japan) positive asymptomatic ddCHoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, AIDS, (Camden, NJ)ARC (protease inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville,GA) Efavirenz DuPont HIV infection, AIDS, (SUSTIVA ®), (DMP 266) MerckARC (STOCRIN ®) (-)6-Chloro-4(S)- (non-nucleoside RT cyclopropylethynyl-inhibitor) 4(S)-trifluoro-methyl- 1,4-dihydro-2H-3,1- benzoxazin-2-one,Famciclovir Smith Kline herpes zoster, herpes simplex FTC EmoryUniversity HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GS840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GW141 Glaxo Welcome HIV infection, AIDS, ARC (protease inhibitor) GW 1592Glaxo Welcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor)HBY097 Hoechst Marion HIV infection, AIDS, Rousell ARC (non-nucleosidereverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection,AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's InterferonBeta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon SciencesARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC Compound A Merck HIVinfection, AIDS, ARC, asymptomatic HIV positive ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc.diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC(reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-MyersSquibb CMV infection Nelfinavir Agouron HIV infection, AIDS,Pharmaceuticals ARC (protease inhibitor) Nevirapine BoeheringerIngleheim HIV infection, AIDS, ARC (protease inhibitor) NovaprenNovaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula LabsAIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMVretinitis, HIV Phosphonoformate Products, Inc infection, other CMVinfections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC(protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4Sheffield Med. Tech HIV infection, AIDS, (Houston TX) ARC RitonavirAbbott HIV infection, AIDS, ARC (protease inhibitor) SaquinavirHoffmann-LaRoche HIV infection, AIDS, ARC (protease inhibitor)Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy-ARC thymidine T-20 Trimeris HIV infection, AIDS, ARC Valaciclovir GlaxoWellcome genital HSV & CMV infections Virazole Viratek/ICN asymptomaticHIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC Amprenivir Vertex HIVinfection, AIDS, VX-478 ARC Zalcitabine Hoffmann-La Roche HIV infection,AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS,ARC, Kaposi's sarcoma, in combination with other therapies ABT-378Abbott HIV infection, AIDS, ARC (protease inhibitor) JE2147/AG1776Agouron HIV infection, AIDS, ARC (protease inhibitor) T-20 Trimeris HIVinfection, AIDS, T-1249 ARC (fusion inhibitor) BMS 232632Bristol-Myers-Squibb HIV infection, AIDS, ARC (protease inhibitor)IMMUNO-MODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohnadvanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10Elan Corp, PLC HIV infection (Gainesville, GA) Gamma InterferonGenentech ARC, in combination w/TNF (tumor necrosis factor) GranulocyteGenetics Institute AIDS Macrophage Colony Sandoz Stimulating FactorGranulocyte Hoeschst-Roussel AIDS Macrophage Colony Immunex StimulatingFactor Granulocyte Schering-Plough AIDS, combination Macrophage Colonyw/AZT Stimulating Factor HIV Core Particle Rorer seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-La Roche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts(aldeslukin) Immune Globulin Cutter Biological pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcomaMuramyl-Tripeptide Granulocyte Amgen AIDS, in combination ColonyStimulating w/AZT Factor Remune Immune Response immunotherapeutic Corp.rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS,ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combinationw/AZT SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute Tumor Necrosis GenentechARC, in combination Factor; TNF w/gamma Interferon etanercept ImmunexCorp rheumatoid arthritis (Enbrel ®) infliximab Centocor rheumatoidarthritis and (Remicade ®) Crohn's disease ANTI-INFECTIVES Clindamycinwith Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer cryptococcalmeningitis, candidiasis Pastille Squibb Corp. prevention of NystatinPastille oral candidiasis Ornidyl Merrell Dow PCP EflornithinePentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL)Trimethoprim antibacterial Trimethoprim/sulfa antibacterial PiritreximBurroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCPprophylaxis isethionate for inhalation Spiramycin Rhone-Poulenccryptosporidial diarrhea Intraconazole- Janssen Pharm. histoplasmosis;R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCP OTHERDaunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human OrthoPharm. Corp. severe anemia Erythropoietin assoc. with AZT therapyRecombinant Human Serono AIDS-related wasting, Growth Hormone cachexiaLeukotriene B4 — HIV infection Receptor Antagonist Megestrol AcetateBristol-Myers Squibb treatment of anorexia assoc. w/AIDS Soluble CD4Protein — HIV infection and Derivatives Testosterone Alza, Smith KlineAIDS-related wasting Total Enteral Norwich Eaton diarrhea and NutritionPharmaceuticals malabsorption related to AIDS

[0376] It will be understood that the scope of combinations of thecompounds of this invention with AIDS antivirals, immunomodulators,anti-infectives or vaccines is not limited to the list in the aboveTable, but includes in principle any combination with any pharmaceuticalcomposition useful for the treatment of AIDS.

[0377] Preferred combinations are simultaneous or alternating treatmentswith a compound of the present invention and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl.Preferred agents for combination therapy include: Zidovudine,Lamivudine, Stavudine, Efavirenz, Ritonavir, Nelfinavir, Abacavir,Indinavir, 141-W94 (4-amino-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide),N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-N′(t-butylcarbox-amido)-piperazinyl))-pentaneamide,and Delavirdine. A preferred inhibitor of HIV protease is indinavir,which is the sulfate salt ofN-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N′-(t-butylcarbo-xamido)-piperazinyl))-pentane-amideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred inhibitors of HIV protease include nelfinavir andritonavir. Preferred non-nucleoside inhibitors of HIV reversetranscriptase include (−)6-chloro-4(S)-cyclopropylethynyl4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,which may be prepared by methods disclosed in EP 0,582,455. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations with thecompounds of the present invention include the following: (1) Zidovudineand Lamivudine; (2) Stavudine and Lamivudine; (3) Efavirenz; (4)Ritoavir; (5) Nelfinavir; (6) Abacavir; (7) Indinavir; (8) 141-W94; and(9) Delavirdine. Preferred combinations with the compounds of thepresent invention further include the following (1) indinavir, withefavirenz or (-) 6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, and, optionally, AZT and/or 3TCand/or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddI and/orddC.

[0378] Compound A in the foregoing Table isN-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))pentaneamide,preferably administered as the sulfate salt. Compound A can be preparedas described in U.S. Pat. No. 5646148.

[0379] In such combinations the compound of the present invention andother active agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

[0380] The compounds of the present invention may be administered byoral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

[0381] The pharmaceutical compositions for the administration of thecompounds of this invention may conveniently be presented in dosage unitform and may be prepared by any of the methods well known in the art ofpharmacy. All methods include the step of bringing the active ingredientinto association with the carrier which constitutes one or moreaccessory ingredients. In general, the pharmaceutical compositions areprepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier or a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases. As used herein, theterm “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients in the specified amounts.

[0382] The pharmaceutical compositions containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

[0383] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin, orolive oil.

[0384] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0385] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0386] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0387] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0388] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

[0389] The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

[0390] The compounds of the present invention may also be administeredin the form of suppositories for rectal administration of the drug.These compositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0391] For topical use, creams, ointments, jellies, solutions orsuspensions, etc., containing the compounds of the present invention areemployed. (For purposes of this application, topical application shallinclude mouthwashes and gargles.) The pharmaceutical composition andmethod of the present invention may further comprise othertherapeutically active compounds as noted herein which are usuallyapplied in the treatment of the above mentioned pathological conditions.

[0392] In the treatment or prevention of conditions which requirechemokine receptor modulation an appropriate dosage level will generallybe about 0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day.

[0393] It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

[0394] Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made from known procedures or as illustrated.

[0395] The preparation of cinnamate esters such as 1-3 as intermediatesthat can be used for the synthesis of compounds within the scope of theinstant invention is detailed in Scheme 1. Cinnamate esters of structure1-3 can be obtained commercially or can be synthesized by reacting asuitable aromatic aldehyde 1-1 with a phosphonoacetate such as 1-2 inthe presence of sodium hydride or other bases such as sodium, lithium orpotassium hexamethyldisilazide, potassium t-butoxide, and the like. Thealdehyde 1-1 can be obtained commercially or can be prepared in avariety of ways from commercial materials (see March J. “AdvancedOrganic Chemistry”, 4th ed., John Wiley & Sons, New York, pp. 1270-1271(1992)).

[0396] A preparation of cyclopentane intermediates having a C4 arylsubstituent within the scope of the instant invention is detailed inScheme 2 and can be used to prepare non-racemic cyclopentane derivativeswhen the resolution steps are done. Treatment of a trans-cinnamic estersuch as 2-1 (see Scheme 1) with 2-((trimethylsilyl)methyl)-2-propen-1-ylacetate (2-2) in the presence of a catalytic amount oftetrakis(triphenylphosphine) palladium (0) and1,2-bis(diphenylphosphino)ethane in THF at reflux afforded theexo-methylene cyclopentane 2-3. Hydrolysis of the ester can be doneseveral ways, such as with aqueous sodium or lithium hydroxide inmethanol or THF, to obtain the racemic acid 24. Resolution of theenantiomers can be accomplished by fractional crystallization fromisopropanol, or other suitable solvents, of the salts with either(R)-(+)- or (S)-(−)-α-methylbenzyl amine to give the salts 2-5 and 2-6.The non-racemic acids 2-7 and 2-8 are recovered by acidification andextraction. Reesterification to non-racemic 2-9 and 2-10 can be done ina variety of ways, such as with trimethylsilyldiazomethane or acidcatalyzed esterification in methanol.

[0397] An alternative preparation of non-racemic cyclopentaneintermediates having a C-4 aryl substituent within the scope of theinstant invention is detailed in Scheme 2A. Conversion of thecyclopentane acid 2-4 to the acid chloride 2-11 under standardconditions, such as with oxalyl chloride in methylene chloride with acatalytic amount of DMF, or to the mixed anhydride 2-12, prepared insitu with trimethylacetyl chloride in ether with TEA as base, followedby reaction with the preformed lithium salt of(S)-(−)-4-benzyl-2-oxazolidinone 2-13, afforded the two non-racemicdiastereomeric products 2-14 and 2-15, which are then separable bychromatography. Hydrolysis of each diastereomer under standardconditions, such as with lithium hydroxide and hydrogen peroxide ortrimethylamine-N-oxide, affords the two non-racemic acids 2-7 and 2-8.Alternatively, in order to obtain an enhanced amount of the desireddiastereomer 2-14 before separation, similar conversion of the startingtrans -cinnamic acid 2-16 (Scheme 1) to the chiral trans-cinnamate 2-17followed by the ring formation reaction with2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (2-2) as detailed inScheme 2 affords a 60:40 product mixture of 2-14:2-15.

[0398] Preparation of some 1,3,4-trisubstituted cyclopentanes within thescope of the instant invention is given in Scheme 3. Reduction of ester3-1 (either racemic or non-racemic) (Scheme 2), for example, withlithium borohydride, diisobutylaluminum hydride, lithium aluminiumhydride, or sodium bis(2-methoxyethoxy)aluminum hydride in a suitablesolvent, such as ether or THF, provides the primary alcohol 3-3.Alternatively, reduction of the acid 3-2 (either racemic or non-racemic)(Scheme 2 or 2A), for example with lithium aluminium hydride in THF,will also afford the alcohol 3-3. In cases where the Ar moiety is notamenable to salt resolution as detailed in Scheme 2, an alternativeresolution can often be achieved using chiral HPLC methods to separatethe enantiomers of 3-3. Oxidation of 3-3 to the aldehyde 3-4 can becarried out under numerous conditions, such as with DMSO and oxalylchloride at low temperature, followed by triethylamine (Swernoxidation), with the Dess-Martin periodinane, with N-methylmorpholine inthe presence of a catalytic amount of TPAP, or with various chromiumtrioxide-based reagents (see March J. “Advanced Organic Chemistry”, 4thed., John Wiley & Sons, New York, pp. 1167-1171 (1992)). Reductivealkylation of a cyclic amine, such as piperidine 3-5 (see Schemes 12 to29), using for example sodium triacetoxyborohydride or sodiumcyanoborohydride in a suitable solvent such as methylene chloride,1,2-dichloroethane, THF, acetonitrile or methanol, with 3-4 thenprovides a 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentanederivative 3-6. In the cases where the R group of the piperidine isstable to ozone, ozonolysis of the exo-methylene followed by a reductivework-up with dimethyl sulfide affords the ketone 3-7. Alternatively, 3-7can be obtained from 3-6 through a stepwise oxidation using catalyticosmium tetroxide in the presence of N-methylmorpholine-N-oxide followedby sodium periodate cleavage of the intermediate diol. A secondreductive alkylation of a D- and/or L-amino-acid ester, such as themethyl, ethyl, t-butyl, benzyl or 4-methoxybenzyl ester of glycine(R″=H), alanine (R″=Me), valine (R″=iso-Pr), leucine (R″=iso-Bu),isoleucine (R′=sec-Bu), cyclopropylalanine (R″=CH₂cycPr),cyclobutylalanine (R″=CH₂cycBu), cyclohexylglycine (R″=cycHex) or aN-alkyl amino-acid, such as N-methyl glycine (R′=Me), or a cyclicamino-acid, such as proline (R′R″=—(CH₂)₃—), with 3-7 as described abovewith sodium triacetoxyborohydride or sodium cyanoborohydride affords3-8. Final deprotection of the ester under conditions to which the Rgroup is stable, such as HCl in ether, TFA or formic acid for t-butyland 4-methoxybenzyl esters, hydrogenation for benzyl esters or standardhydrolysis for alkyl or benzyl esters, affords the final product(s) 3-9which are within the scope of the instant invention and which can bechemokine receptor modulators. The two individual C-1 isomers (fourdiastereomers when either the cyclopentyl scaffold or the amino-acid areracemic) can be separated by flash chromatography, Prep TLC or HPLCmethods as either the penultimate esters 3-8 and/or the final compounds3-9.

[0399] An alternative route for the preparation of some 1,3,4-trisubstituted cyclopentanes within the scope of the instant invention isgiven in Scheme 4. In the cases where the R group of the piperi dine inScheme 3 is not stable to ozone or the osmium tetroxide/sodium periodatesequence, oxidation of the exo-methylene can be done prior to thereductive alkylation of the piperidine. Thus, ozonolysis of the alcohol4-1 (Scheme 3) followed by a reductive work-up with dimethyl sulfideaffords the ketone-alcohol 4-2. Oxidation to the ketone-aldehyde 4-3 canbe done as described for Scheme 3 with N-methylmorpholine/TPAP or underSwern conditions. Selective reductive alkylation of the 4-substitutedpiperidine 4-4 (see Schemes 12 to 29) with the aldehyde of 4-3, usingfor example sodium triacetoxyborohydride or sodium cyanoborohydride in asuitable solvent such as methylene chloride, 1,2-dichloroethane, THF,acetonitrile or methanol, then provides the3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 4-5 (sameas 3-7). This can then be converted to the final product(s) 4-6 asdescribed in Scheme 3.

[0400] An alternative route for the preparation of some1,3,4-trisubstituted cyclopentanes within the scope of the instantinvention is given in Scheme 5. Reductive alkylation with ketone alcohol5-1 (Scheme 4) of a variety of amino-acid esters (See Scheme 3) affordsthe alcohols 5-2 and 5-3, of which 5-2 is the major product (lower R_(f)when R″ is (S), higher R_(f) when R″ is (R)) and 5-3 is the minorproduct (higher R_(f) when R″ is (S), lower R_(f) when R″ is (R)).Separation of the individual diastereomers (2 when both reactants arenon-racemic, 4 when only one is non-racemic) can be done at thisintermediate or at a later step. Oxidation of 5-2 and/or 5-3 to thealdehyde(s) 5-4 can be done as described in Scheme 3, preferably nowwith N-methylmorpholine/TPAP due to the presence of the secondary N—H.Reductive alkylation of a 4-substitutedpiperidine 5-5 (see Schemes 12 to29) with the aldehyde of 5-4, using for example sodiumtriacetoxyborohydride or sodium cyanoborohydride in a suitable solventsuch as methylene chloride, 1,2-dichloroethane, THF, acetonitrile ormethanol, then provides the3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 5-6. Theintermediate ester(s) 5-6 can then be converted to the final product(s)5-7 as described in Scheme 3.

[0401] An alternative preparation of the intermediates 5-2 and 5-3 inScheme which reverses the C-1 isomeric selectivity is shown in Scheme5A. Silylation of the alcohol moiety of 5-1 (Scheme 4) gives the silylether 5-10. Alternatively, silylation of the alcohol 5-8 (Scheme 3)gives 5-9 which on ozonolysis can also afford the silyl ether 5-10.Reductive alkylation of the aforementioned amino-acid esters now usingthe silyl ether 5-10 affords the products 5-11 and 5-12 in anessentially opposite ratio as is obtained in Scheme 5 for 5-2 and 5-3.TBAF desilylation then affords primarily 5-3. Thus, the preferred C-1orientation can be selected for depending on the requirements of thedesired final compounds.

[0402] An alternative preparation of the intermediates 5-2 or 5-3 inScheme 5 and intermediates 5-11 and 5-12 in Scheme 5A when R′ is Me isshown in Scheme 5B. When 5-13 is formed in the reductive amination withketones 5-1 (R_(b)=H) or 5-10 (R_(b)=TBDMS), a second reductiveamination of 5-13 with formaldehyde, either in the presence of hydrogenand a suitable catalyst, such as 10% Pd/C or Pearlman's catalyst, inmethanol or standard reaction with sodium triacetoxyborohydride in1,2-dichloroehthane, affords the methylated intermediates 5-14. Theseintermediates can be further elaborated to the final products asdescribed in Scheme 5 and/or 5A.

[0403] An alternative route for the preparation of some1,3,4-trisubstituted cyclopentanes within the scope of the instantinvention is given in Scheme 6.

[0404] Reductive alkylation of benzylamine with ketone-alcohol 6-1(Scheme 4, either racemic or non-racemic), using for example sodiumtriacetoxyborohydride or sodium cyanoborohydride, gives 6-2 which can behydrogenated under standard conditions in methanol in the presence of apalladium catalyst, for example Pd/C or Pearlman's catalyst and usingeither hydrogen under pressure or ammonium formate at reflux, to affordthe primary amine 6-3. Reaction of the amine with CBZ chloride or Bocanhydride gives the amine protected carbamates 6-4 and 6-5 as a mixtureof C-1 isomers which can be separated. Oxidation to the aldehydes 6-6and 6-7 is carried out under Swern conditions or withN-methylmorpholine/TPAP. The relative stereochemistry of the C-1 to theC-3 and C-4 substituents was determined by NMR Noe experiments on eitherthe alcohols 6-4 and 6-5 or the aldehydes 6-6 and 6-7. Reductivealkylation of a 4-substitutedpiperidine 6-8 with the individualaldehydes 6-6 and 6-7, using for example sodium triacetoxyborohydride orsodium cyanoborohydride in a suitable solvent such as methylenechloride, 1,2-dichloroethane, THF, acetonitrile or methanol, thenprovides each of the C-1 amino-protected isomeric 3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivatives 6-9 and 6-10.Deprotection of the C-1 amino with either TFA (for R_(a)=t-butyl) orstandard hydrogenation (for R_(a)=Bn) depending on the stability of thepiperidine R group affords the amines 6-11 and 6-12. These amines canthen be individually reductively alkylated as above with 2-oxo-aceticacids, such as 2-oxovaleric (R″=n-Pr), 4-methyl-2-oxovaleric(R″=iso-Bu), 2-oxophenylacetic (R″=Ph), to afford the final compounds6-13 and 6-14 and 6-15 and 6-16 as mixtures of the R” isomers. In thecase of R″=iso-Bu and non-racemic cyclopentyl scaffold, comparison ofthe HPLC of these products with those obtained in Scheme 5 allowed thestereochemical assignments of all the final products and intermediates.

[0405] An alternative route for the preparation of some1,3,4-trisubstituted cyclopentanes within the scope of the instantinvention is given in Scheme 7. Reductive alkylation, using for examplesodium triacetoxyborohydride or sodium cyanoborohydride, of an alkylamine with the ketone 7-1 (Schemes 3 or 4) gives 7-2 as a mixture of C-1isomers which may be separated. Alternatively, carbamate 7-3 (see Scheme6) can be alkylated with an alkyl or allyl halide, such as1-bromo-2-methylprop-2-ene, and a strong base, such as sodium hydride inDMF, followed by hydrogenation under standard conditions to reduce theallyl. When Ra is Bn, removal the CBZ can occur simultaneously to givethe same amine intermediate 7-2. When R_(a) is t-butyl, a subsequentreaction with TFA is required to give 7-2. Alkylation of the amine witht-butyl or benzyl bromoacetate affords 7-5 which can be converted to thedesired final compound(s) 7-6 as described in Scheme 3.

[0406] An alternative route for the preparation of some1,3,4-trisubstituted cyclopentanes within the scope of the instantinvention is given in Scheme 8. Reductive alkylation, using for examplesodium triacetoxyborohydride or sodium cyanoborohydride, of glycinet-butyl, benzyl or PMB ester with the ketone-alcohol 8-1 (Scheme 4)gives 8-2 as a mixture of C-1 isomers. A second reductive alkylationwith a ketone or aldehyde affords the N-alkyl glycine derivatives 8-3and 8-4 which can be separated chromatographically either before and/orafter the second alkylation. Also, the order of the steps can bereversed such that reductive alkylation of an amine with 8-1 first togive 8-5, followed by alkylation with an alkyl or benzyl bromoacetate asin Scheme 7, affords 8-3 and 8-4. These reactions generally give 8-3 asthe predominate product. Individual oxidation of the alcohols 8-3 and8-4 can be done either under Swern conditions or using theN-methylmorpholine/TPAP method to give the aldehyde intermediate(s)followed by a second or third reductive alkylation of a4-substitutedpiperidine 8-6, using for example sodiumtriacetoxyborohydride or sodium cyanoborohydride in a suitable solventsuch as methylene chloride, 1,2-dichloroethane, THF, acetonitrile ormethanol, which then provides the3-((4-substitutedpiperidin-1-yl)methyl)cyclopentane derivative 8-7. Thisintermediate can then be converted to the final product(s) 8-8 asdescribed in Scheme 3.

[0407] An alternative preparation of the intermediates 8-3 and 84 inScheme 8 which again reverses the C-1 isomeric selectivity is shown inScheme 8A. Silylation of the alcohol moiety of 8-1 (Scheme 4) gives thesilyl ether 8-9. Alternatively, silylation of the alcohol 8-10 (Scheme3) gives 8-11, which on ozonolysis can also afford the silyl ether 8-9.Reductive alkylation now using the silyl ether 8-9 gives 8-12 and 8-13followed by the second reductive alkylation with an aldehyde or ketoneaffords the products 8-14 and 8-15 in an essentially opposite ratio asis obtained in Scheme 8 for 8-3 and 8-4. TBAF desilylation then affordsprimarily 8-4. Separation of the C-1 isomers can usually be achieved atone or more of the intermediate steps. Thus, the preferred C-1orientation can be selected for depending on the requirements of thedesired final compounds.

[0408] Several other alternative routes for the preparation of some1,3,4-trisubstituted cyclopentanes within the scope of the instantinvention are given in Scheme 9. Reductive alkylation, using for examplesodium triacetoxyborohydride or sodium cyanoborohydride, of anamino-acid ester having dialkyl substitution with the ketone-alcohol 9-1(Scheme 4) gives 9-2 as a mixture of C-1 isomers which may be separatedand carried on to the final product(s) 9-3 individually or as a mixtureas detailed in Scheme 5. Alternatively, a second reductive alkylation of9-2 as in Scheme 8 affords 9-4 which may be separable or used as amixture to give final product(s) 9-5. Also, more extended amino-acidesters, such as a -alanine ester (9-6, n=1) or 4-aminobutyrate (9-6,n=2), which may also be substituted on the chain or on N, can beemployed to give 9-7. These intermediates can then be converted to finalproduct(s) 9-8 as described in Scheme 5 and/or 8.

[0409] An alternative route for the preparation of some1,3,4-trisubstituted cyclopentanes within the scope of the instantinvention is given in Scheme 10. Reductive alkylation, using for examplesodium triacetoxyborohydride or sodium cyanoborohydride, of a cyclicsecondary amino-acid 10-1, such as D- or L-proline t-butyl ester (n=0),β-proline t-butyl ester (n=0), 2-, 3-, and 4-t-butylcarboxypiperidine(n=1), with the ketone-alcohol 10-2 (Scheme 4) gives 10-3 and 10-4 as amixture of C-1 isomers which may be separated. These intermediates canthen be converted to the final product(s) as described in Scheme 5.

[0410] An alternative route for the preparation of some1,3,4-trisubstituted cyclopentanes within the scope of the instantinvention is given in Scheme 11. Reductive alkylation, using for examplesodium triacetoxyborohydride or sodium cyanoborohydride, of a cycloalkylamino-acid 11-1, such as 1-aminocyclopentane carboxylic acid t-butylester (Z=single bond) or a heterocyclic amino-acid, such as4-aminomorpholin-2-yl carboxylic acid t-butyl ester (Z=0) with theketone-alcohol 11-2 (Scheme 4) gives 11-3 and 11-4 as a mixture of C-1isomers which may be separated. These intermediates can then beconverted to the final product(s) as described in Scheme 5.

[0411] One method of generating 4-aryl piperidines as intermediates isgiven in Scheme 12. Reaction of commercially available 12-1 or 12-2 witha strong base, such as LDA, LHDMS, NaHMDS, KHMDS, or NaH followed bytreating with a suitable triflating agent, such as 5-chloropyrid-2-yltriflimide (12-3), N-phenyl triflimide or triflic anhydride, providesenol triflates 12-4 or 12-5. Heating with commercially available arylboronic acids in the presence of a suitable palladium(0) catalyst suchas tetrakis triphenylphosphine palladium, a base (such as potassiumcarbonate or sodium carbonate), in a solvent such as DME, THF, dioxaneor toluene/ethanol, effects coupling to provide the unsaturated products12-6 or 12-7. In the case of 12-7, treatment with a heterogeneouspalladium catalyst in methanol or ethanol in an atmosphere of hydrogenprovides the desired intermediate 12-8. Alternatively, the Boc protectedderivative 12-6 is hydrogenated under standard conditions to providedthe saturated piperidine 12-9, which is then deprotected under acidicconditions (such as trifluoroacetic acid and anisole in methylenechloride or HCl in methanol), to provide 12-8 as a salt, which is thenutilized as the cyclic secondary amine component as shown above inSchemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0412] An alternative method of generating 4-aryl piperidines asintermediates is given in Scheme 13. Reaction of commercially available13-1 with an aryl magnesium halide or with an aryllithium (in thepresence or absence of anhydrous cerium trichloride) provides tertiaryalcohol 13-2, which upon treatment under acidic conditions (such assulfuric acid, HBr in acetic acid, HCl in acetic acid) or underdehydrating conditions (such as with thionyl chloride in pyridine orwith phosphorus oxychloride) provides olefin 13-3. Hydrogenation understandard conditions using either hydrogen gas or a hydrogen donor (suchas ammonium formate or cyclohexene) effects reduction of the double bondand cleavage of the N-benzyl group to provide the desired intermediate13-4. Under some circumstances it may be preferable to reduce the doublebond under non -hydrogenolytic conditions, for example withtriethylsilane and trifluoroacetic acid or under dissolving metalconditions (for example, sodium or lithium metal in ammonia or a loweralkyl amine). If the N-benzyl group is not removed under theseconditions, it may be cleaved by treatment with either vinylchloroformate and then hydrogen chloride or by treatment with2-chloroethyl chloroformate followed by heating in methanol. The product134 is then utilized as the cyclic secondary amine component as shownabove in Schemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0413] One route for the preparation of4-hydroxy-4-(3-arylpropyl)piperidines is given in Scheme 14. Treatmentof commercially available 4-piperidones 14-1 or 14-2 withtrimethylsulfonium iodide and sodium hydride in dimethyl sulfoxide at orabove room temperature provides Spiro epoxides 14-3 or 14-4. Addition ofthe lithium salt of trimethylsilylacetylene to these epoxides in thepresence of lithium perchlorate in THF at 0 degrees C., followed bytreatment of the crude intermediate with potassium carbonate inmethanol, affords the acetylenic alcohols 14-5 or 14-6. Heating of thesealkynes with an aromatic halide or triflate in the presence of copper(I)iodide, a palladium catalyst such as bis(triphenylphosphine)palladiumdichloride or bis(triphenylphosphine)palladium diacetate in the presenceof a tertiary amine base such as triethylamine or tributylamine, thenprovides coupling products 14-7 or 14-8. In the case of the N-benzylprotected intermediate 14-8, hydrogenation/hydrogenolysis under standardconditions (for example 10% Pd/C in an atmosphere of hydrogen) providesdesired intermediate 14-9. For the Boc protected species 14-7,hydrogenation as above provides the saturated piperidine 14-10, andtreatment of this compound under anhydrous acidic conditions (forexample, trifluoroacetic acid and anisole in methylene chloride, oracetyl chloride in methanol) then yields the salt of intermediate 14-9.This compound is then utilized as the cyclic secondary amine componentas shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11. Alternatively, if4-piperidone is attached directly to the functionalizedalkylcyclopentane framework described above and no functionality in thealkylcyclopentane would be affected, then the chemistry described hereincan be carried out treating the aforementioned alkylcyclopentane segmentas ‘P’ given in Scheme 14.

[0414] An alternative route for the preparation of4-hydroxy-4-(3-arylpropyl)piperidines is given in Scheme 15. Treatmentof commercially available 4-piperidones 15-1 or 15-2 with a suitableallyl metal compound (such as allylmagnesium bromide orallyltributylstannane (in the presence of boron trifluoride etherate) inTHF, ether or dichloromethane, provides adducts 15-3 or 15-4.Hydroboration with a dialkylborane, such as 9-borabicyclo[3.3.1]nonane(9-BBN), followed by treatment with an aryl halide (the halidespreferably being bromide or iodide) or aryl triflate and sodiummethoxide in the presence of a suitable soluble palladium catalyst, forexample Pd(dppf)Cl₂, in warm to refluxing THF, provides the 3-arylpropylderivatives 15-5 and 15-6. For benzylamine 15-6, hydrogenolysis understandard conditions provides the desired intermediate 15-7. For Bocsubstituted piperidine 15-5, exposure to suitable anhydrous acidicconditions (for example trifluoroacetic acid and anisole in methylenechloride or HC in methanol at temperatures from 0-25 degrees C) affordsthe salt of 15-7. This compound is then utilized as the cyclic secondaryamine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11.Alternatively, if no functionality are present in the alkylcyclopentaneframework that would be adversely effected by the above mentionedchemistry, then 4-piperidone may be attached directly to thealkylcyclopentane framework described above, and the chemistry describedin this paragraph can be carried out equating the alkylcyclopentanesegment to the group ‘P’ given in Scheme 15, structures 1 through 6.

[0415] A route for the preparation of 4-(3-arylpropyl)piperidines isgiven in Scheme 16. Treatment of phosphonoacetate 16-1 with KHMDSfollowed by addition of commercially available N-Boc 4-piperidone 16-2provides unsaturated ester 16-3. Hydrogenation of 16-3 followed byhydrolysis to the acid and then reduction with borane.ethyl sulfide thenaffords primary alcohol 164. Mild oxidation of 16-4 under Swemconditions provides the corresponding aldehyde, which upon treatmentwith the Wittig reagent prepared from methyltriphenylphosphonium iodideand KHMDS yields olefin 16-5. Hydroboration with a dialkylborane, suchas 9-borabicyclo[3.3.1]nonane (9-BBN), followed by treatment with anaryl halide (the halides preferably being bromide or iodide) or aryltriflate in the presence of a suitable soluble palladium catalyst, forexample PdCl₂DPPF, in warm to refluxing THF, provides the 3-arylpropylderivative 16-6. Removal of the Boc group under acidic conditions, forexample with HCl in methanol or with trifluoroacetic acid in methylenechloride, then affords the 1-unsubstituted piperidine 16-7, which canthen be employed as the secondary amine component in the synthesesdescribed above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0416] Another route for the preparation of 4-(3-arylpropyl)piperidinesis given in Scheme 17. Treatment of phosphonoacetate 17-1 with KHMDSfollowed by addition of commercially available N-Boc-4-piperidone 17-2provides unsaturated ester 17-3. Hydrogenation of 17-3 followed byhydrolysis to the acid and then reduction with borane.methyl sulfidethen affords primary alcohol 17-4. Formation of the alkyl iodide withtriphenylphosphine and iodine in the presence of imidazole followed bytreatment with triphenylphosphine provides phosphonium salt 17-5.Deprotonation with a suitable base, for example, KHMDS, LiHMDS, NaHMDS,NaH, LDA, or KH affords the Wittig agent in situ, which upon treatmentwith a suitable aromatic aldehyde yields the unsaturated derivative17-6. Hydrogenation under standard conditions provides 17-7, and removalof the Boc group with HCl in methanol or with other acidic conditionsthen provides the 1-unsubstituted piperidine 17-8, which can then beemployed as the secondary amine component in the syntheses describedabove in Schemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0417] Preparation of piperidines with a 4-(3-aryl-3,3,-difluoropropyl)side chain is given in Scheme 18. Treatment of commercially available18-1 with Boc anhydride provides protected piperidine 18-2. Oxidation,for example with the Dess-Martin reagent, by a Swern oxidation, or otherknown methods provides aldehyde 18-3. Condensation underHomer-Wadsworth-Emmons conditions affords unsaturated ester 18-4, whichis hydrogenated to ester 18-5 and then hydrolysed to acid 18-6.Formation of the N-methyl-N-methoxy amide 18-7 is carried out employingstandard activating agents such as EDC. Weinreb amide 18-7 is thenallowed to react with an arylmetal reagent, such as an aryl magnesiumhalide or an aryllithium, to provide ketone 18-8. Cleavage of theprotecting Boc group under acidic conditions yields 18-9, which isreprotected with a carbobenzyloxy group under standard conditions, toafford 18-10. Formation of dithiolane 18-11 with ethanedithiol and borontrifluoride is followed by treatment with1,3-dibromo-3,3-dimethylhydantoin and pyridine-hydrogen fluoride complexat or around −78 degrees C., to provide gem-difluoro derivative 18-12.Removal of the CBZ group under reductive conditions provides piperidine18-13, which may be employed directly as the secondary amine inchemistry described above. Alternatively, if additional purification isdesired, 18-13 may be protected with a Boc group to afford 18-14. Aftersuitable purification, the Boc group is removed under acidic conditionsat or near 0 degrees C. A controlled, basic work-up then provides 18-13,suitable for use as described above in Schemes 3, 4, 5, 6, 8, 9, 10 and11.

[0418] A route for the preparation of 4-(3-arylpropyl)piperidines isgiven in Scheme 19. Treatment of phosphonoacetate 19-1 with KHMDSfollowed by addition of commercially available N-Boc-4-piperidone 19-2provides unsaturated ester 19-3. Hydrogenation of 19-3 followed byhydrolysis to the acid and then reduction with borane-methyl sulfidethen affords primary alcohol 19-4. Mild oxidation of 194 under Swernconditions provides the corresponding aldehyde, which upon treatmentwith the Wittig reagent prepared from methyltriphenylphosphonium iodideand KHMDS yields olefin 19-5. Palladium-catalyzed arylation of 19-5 thenaffords unsaturated derivative 19-6. Addition of dibromocarbene(generated in situ from bromoform and potassium hydroxide) providescyclopropyl derivative 19-7. Debromination is carried out by slowaddition of tributyltin hydride in the presence of the radical initiatorAIBN. Removal of the nitrogen protecting group under acidic conditions,for example, hydrochloric acid in methanol, affords cyclopropylpiperidine 19-8, which can then be employed as the secondary aminecomponent in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9,10 and 11.

[0419] A route for the preparation of4-(3-aryl-2-methylpropyl)piperidines is given in Scheme 20. Treatment ofcommercially available 3-chloropropionic acid (20-1) withtriphenylphosphine in refluxing toluene provides phosphonium salt 20-2.Treatment with sodium hydride in DMSO/THF provides the ylide in situ,which upon addition of piperidone 20-3 affords the adduct 20-4.Reduction of the double bond, for example with hydrogen gas in thepresence of a palladium catalyst, gives acid 20-5. Treatment of 20-5with trimethylacetyl chloride and triethylamine generates the mixedanhydride in situ, which upon treatment with the lithium salt of4-(S)-benzyl-2-oxazolidone yields 20-6. Deprotonation of 20-6 withsodium hexamethyldisilazide, followed by addition of methyl iodide,provides alpha-methyl derivative 20-7. Reduction of acyl-oxazolidone20-7 with lithium borohydride produces the corresponding primaryalcohol, which is converted to primary iodide 20-8 with iodine,triphenylphosphine and imidazole in toluene. Coupling with phenylmagnesium bromide in the presence of Ni(fdpp)Cl₂ affords aralkylderivative 20-9, which is then deprotected under acidic conditions toprovide piperidine 20-10. Piperidine 20-10 can then be employed as thesecondary amine component in the syntheses described above in Schemes 3,4, 5, 6, 8, 9, 10 and 11.

[0420] A route for the preparation of4-(3-aryl-1-methylpropyl)piperidines is given in Scheme 21. Addition ofthe anion of phosphonoester 21-1 to piperidone 21-2 provides unsaturatedester 21-3. Reduction of the double bond and hydrolysis of the esteraffords acid 21-4. Treatment of 21-4 with triethylamine andtrimethylacetyl chloride provides the mixed anhydride in situ, which isthen coupled with the lithium salt of 4-(S)-benzyl-2-oxazolidone, toyield acyl oxazolidone 21-5. Deprotonation with sodiumhexamethyldisilazide followed by addition of methyl iodide provides21-6. Reduction of 21-6 with lithium borohydride affords alcohol 21-7,which upon treatment with iodine, triphenylphosphine and imidazole intoluene is converted to iodide 21-8. Treatment with triphenylphosphinegives phosphonium salt 21-9, which is converted to the ylide withpotassium hexamethyldisilazide. Addition of an aryl aldehyde generatesunsaturated aryl derivative 21-10. Hydrogenation provides saturatedpiperidine 21-11, which is then deprotected under acidic conditions toafford 21-12, which can then be employed as the secondary aminecomponent in the syntheses described above in Schemes 3, 4, 5, 6, 8, 9,10 and 11.

[0421] A route for the preparation of4-(3-aryl-3-methylpropyl)piperidines is given in Scheme 22. Treatment ofcommercially available 4-(R)-phenylbutyric acid (22-1) with ethylchloroformate and triethylamine forms the asymmetric anhydride in situ,which upon treatment with sodium borohydride provides primary alcohol22-1. Alternatively, this conversion can be carried out by treatment of22-1 with borane-THF. Activation of the hydroxy group of 22-2 withmethanesulfonyl chloride in the presence of a hindered base such asN,N-(diisopropyl)ethylamine, followed by displacement with sodium iodidein refluxing acetone affords iodide 22-3. Heating withtriphenylphosphine in toluene provides the phosphonium salt 22-4.Deprotonation of this salt with a strong base, for example n-butyllithium generates the Wittig reagent in situ, which is then allowed toreact with N-Boc-4-piperidone, to yield olefin 22-5. Hydrogenation ofthe double bond followed by treatment with acid, for example HCl inmethanol, then provides the secondary amine salt 22-6, which can then beemployed as the secondary amine component in the syntheses describedabove in Schemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0422] A route for the preparation of4-(3-(benzimidazol-2-yl)propyl)piperidines is given in Scheme 23.Protection of piperidine 23-1 under reductive amination conditionsprovides benzylamine 23-2. Oxidation to aldehyde 23-3 is carried outunder standard conditions, for example with the Dess-Martin periodinane.Addition of ester 23-4 provides unsaturated olefin 23-5, which uponreduction affords ester 23-6. Reduction with lithium aluminum hydride orother strong hydride reducing agents followed by mild oxidation providesaldehyde 23-7. Upon combination with diamine 23-8 under reductivealkylation conditions affords the N-alkylated derivative 23-9. Treatmentwith orthoformate derivative 23-10 in the presence of acid yieldsbenzimidazole 23-11, which upon hydrogenation with palladium on carbonunder transfer hydrogenation conditions generates piperidine 23-12,which can then be employed as the secondary amine component in thesyntheses described above in Schemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0423] Procedures for synthesizing certain CCR5 receptor modulatorscontaining 4-(heteroarylamino)piperidine functionality are shown inScheme 24. After protecting commercially available 4-bromopiperidine,the bromide is displaced with sodium azide, and the azide is reduced,for example by catalytic reduction, to provide aminopiperidine 24-3.Treatment of 24-3 with an aryl or heteroaryl halide (the halidepreferably being bromide) in the presence of a palladium catalyst,sodium t-butoxide and a suitable bidentate ligand (such as BINAP),according to the conditions of Buchwald et al, provides arylamine 24-4.Direct acidic deprotection of 244 may be carried out to providesecondary amine 24-5. Alternatively, amine 244 may be alkylated with asuitable alkyl, alkenyl or alkynyl halide (wherein the halide is bromoor iodo in the case of an alkyl group and chloro or bromo in the case ofallylic or propargylic functionality) in the presence of a strong base,such as potassium hexamethyldisilazide, to provide trisubstituted amine24-6. Acidic deprotection, for example, trifluoroacetic acid and anisolein dichloromethane, or methanolic hydrochloric acid, then provides thebis ammonium salt, which in the case of trifluoroacetic aciddeprotection, is compound 24-7. The secondary piperidines 24-5 and 24-7are then utilized as the cyclic secondary amine component as shown abovein Schemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0424] For certain aminoheterocycles, direct displacement of a halogenmay provide improved access to the desired intermediates. For example,as shown in Scheme 25, unsubstituted and substituted 2-chloropyrimidines25-2 may be coupled directly to amine 25-1 in the presence of a suitablebase, such as triethylamine, to provide aminopyrimidine 25-3. Acidicdeprotection then affords 25-4. Alternatively, 25-3 may be alkylated inthe presence of a strong base to provide 25-5, which upon deprotectiongives intermediate 25-6. The secondary piperidines 25-4 and 25-6 arethen utilized as the cyclic secondary amine component as shown inSchemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0425] One preparation of piperidine subunits containing functionalizedpyrazoles at C4 of the piperidine is given in Scheme 26. Treatment ofpiperidine 26-1 with carbonyldiimidazole to form the acyl imidazole,followed by addition of a dialkyl or alkyl-aryl ketone (26-2) in thepresence of lithium diisopropylamide (LDA) gives the diketone 26-3.Treatment with a monoalkyhydrazine in an alcohol solvent at temperaturesbetween 0 to 100 degrees C. (preferably about 50 degrees C.) in thepresence of a hindered base such as DIPEA then provides a mixture of theisomeric pyrazoles 26-4 and 26-5. After separation of these compounds bychromatography or crystallization, the individual products are deblockedunder acidic conditions (for example trifluoroacetic acid and anisolewith or without methylene chloride as a co-solvent) to provide thepiperidine salts 26-6 and 26-7, which are then used as the cyclicsecondary amine component as shown above in Scheme 2 and in Schemes 3,4, 5, 6, 8, 9, 10 and 11.

[0426] Another preparation of piperidine subunits containingfunctionalized pyrazoles at C4 of the piperidine is given in Scheme 27.Treatment of commercially available bromide 27-1 with triphenylphosphinein refluxing toluene provides phosphonium salt 27-2, which aftertreatment with a strong anhydrous base such as potassiumhexamethyldisilazide in toluene and the piperidine ketone 27-3 providesthe olefin 27-4. Hydroboration followed by an oxidative work-up withchromic acid then affords ketone 27-5. Selective formylation of 27-5with methyl formate in the presence of potassium t-butoxide selectivelyaffords ketoaldehyde 27-6. Heating of 27-6 with a monoalkylhydrazine inmethanol in the presence of a hindered (or insoluble) base such as DIPEAthen provides a mixture of the 1,4-disubstituted pyrazoles 27-7 and27-8. After separation by chromatography, crystallization or fractionaldistillation, the purified isomers are deprotected under transferhydrogenation conditions to provide the piperidines 27-9 and 27-10,which are then utilized as the cyclic secondary amine component as shownabove in Schemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0427] A preparation of piperidine subunits containing3,5-difunctionalized pyrazoles linked through N-1 to C-4 of thepiperidine is given in Scheme 28. Treatment of commercially availablehydrazine 28-1 with diketone 28-2 in ethanol at 0 to 90 degrees C.(preferably 50 degrees C.) in the presence of DIPEA provides a mixtureof pyrazoles 28-3 and 28-4, which are separated under standardconditions, for example HPLC. Removal of the benzyl groups by transferhydrogenation provides the secondary piperidines 28-5 and 28-6, whichare then utilized as the cyclic secondary amine component as shown abovein Schemes 3, 4, 5, 6, 8, 9, 10 and 11.

[0428] A preparation of 4-(benzimidazol-1-yl)piperidine subunits isgiven in Scheme 29. Combining piperidone 29-1 and diamine 29-2 in thepresence of sodium triacetoxyborohydride under dehydrating conditionsprovides reductive amination product 29-3. Addition of a suitablysubstituted ortho ester 29-4 in the presence of a acid catalyst, forexample concentrated hydrochloric acid, provides benzimidazoleintermediate 29-5. Deprotection under reductive conditions, for examplewith palladium on carbon under transfer hydrogenation conditions, thenprovides secondary amine 29-6, which is then utilized as the cyclicsecondary amine component as shown above in Schemes 3, 4, 5, 6, 8, 9, 10and 11.

[0429] Another method of preparing compounds within the scope of theinstant invention is given in Scheme 30 in which most of the chemistryis done on a resin and thus simplifies the isolations. Thus, theketo-acid 30-3, prepared either by standard hydrolysis of the ester 30-1or oxidation of the exo-methylene of 30-2 with ozone in methanol at −70°C. followed by treatment with dimethyl sulfide, is first activated asits anhydride 30-4 by treatment with a dehydrating agent, such asdicyclohexylcarbodiimide or diisopropylcarbodiimde, in a suitablesolvent, such as THF or methylene chloride or a mixture of these, with acatalytic amount of DMAP. Reaction of 30-4 with a suitable sulfonamidelinker 30-5 affords the resin-bound cyclopentanone 30-6. Reductiveamination of various amines with 30-6 affords the resin-bound aminoderivative 30-7. Acylation can be done under standard conditions, suchas with chloroformates, usually in the presence of an amine base, suchas triethylamine, diisopropylethylamine, N-methylmorpholine, orpyridine, to afford the resin-bound amine derivative 30-8. Activation ofthe resin sulfonamide linker with trimethylsilyldiazomethane anddisplacement with an amine, such as the piperidine 30-9 (see Schemes12-29) in which R must be stable to borane-dimethyl sulfide reduction,gives the corresponding amide 30-10. Subsequent reduction of the amide30-10 with borane-dimethyl sulfide and removal of the carbamate, such aswith TFA for a Boc derivative or standard hydrogenation for a CBZderivative, affords the amine 30-11, which can be converted to thedesired final compound as detailed in Scheme 6.

[0430] In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided for the purposeof further-illustration only and are not intended to be limitations onthe disclosed invention.

General

[0431] Concentration of solutions was carried out on a rotary evaporatorunder reduced pressure. Flash chromatography was carried out on silicagel (230-400 mesh). NMR spectra were obtained in CDCl₃ solution unlessotherwise noted. Coupling constants (J) are in hertz (Hz).Abbreviations: diethyl ether (ether), triethylamine (TEA),N,N-diisopropylethylamine (DIEA) saturated aqueous (sat'd), roomtemperature (rt), hour(s) (h), minute(s) (min).

HPLC Conditions

[0432] HPLC A.

[0433] Retention time using the following conditions: Column: YMC ODS A,5 μ, 4.6×50 mm; Gradient Eluant: 10:90 to 90:10 v/v CH₃CN/H₂O+0.5% TFAover 4.5 min, hold 30 sec; Detection: PDA, 210-400 nm; Flow Rate: 2.5mL/min.

[0434] HPLC B.

[0435] Retention time using the following conditions: Column: AnalyticalSales & Services Advantage HL C18 5 μg 4.6×100 mm column; GradientEluant: 10:90 to 90:10 v/v CH₃CN/H₂O+0.5% TFA over 10 min, hold 2 min;Detection: PDA, 200-400 nm; Flow Rate: 2.25 mL/min.

[0436] The following are representative Procedures for the preparationof the piperidines used in the following Examples or which can besubstituted for the piperidines used in the following Examples which maynot be commercially available.

HPLC Conditions

[0437] HPLC A.

[0438] Retention time using the following conditions: Column: YMC ODS A,5 μ 4.6×50 mm; Gradient Eluent: 10:90 to 90:10 v/vacetonitrile/water+0.5% TFA over 4.5 min, hold 30 sec; Detection: PDA,210-400 nm; Flow Rate: 2.5 mL/min.

[0439] HPLC B.

[0440] Retention time using the following conditions: Column: AnalyticalSales & Services Advantage HL C18 5 μ 4.6×100-mm column; GradientEluent: 10:90 to 90:10 v/v acetonitrile/water+0.5% TFA over 10 min, hold2 min; Detection: PDA, 200-400 nm; Flow Rate: 2.25 mL/min.

[0441] The following are representative Procedures for the preparationof the piperidines used in the following Examples or which can besubstituted for the piperidines used in the following Examples and whichare not commercially available.

Procedure 1

[0442] 4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidineDi-Trifluoroacetic Acid Salt

[0443] Step A:1-(1-(t-Butoxycarbonyl)piperidin-4-yl)4-phenylbutane-1,3-dione

[0444] Method A:

[0445] n-Butyl lithium (100 mL, 0.16 mole) was added to a stirredsolution of diisopropylamine (16.16 g, 22.4 mL, 0.16 mole, distilled) inTHF (450 mL) at 0° C. over 45 min under nitrogen. Stirring was continuedfor 10 min at 0° C. after the addition was complete. After cooling to−78° C., phenylacetone (21.45 g, 21.13 mL, 0.16 mole) in THE (100 mL)was added dropwise over 15 min with stirring. This solution was stirredat −78° C. for 1 h. Meanwhile, a solution of N-Boc isonipecotic acid(18.32 g, 0.080 mole) and carbonyl diimidazole (12.98 g, 0.080 mole) inTHF (150 mL) was prepared. After stirring for 15 min, this solution wascanulated into the enolate solution dropwise over 15 min. The reactionwas stirred at <−70° C. for 1 h and then allowed to warm to rt over 3 h.The reaction was quenched with 1M citric acid (250 mL) and stirred for16 h. The organic layer was separated and washed with 250 mL each ofsaturated sodium bicarbonate solution, water and brine. After dryingover sodium sulfate, the organic layer was concentrated to give an oil.The residue was purified by FC on silica gel (10% ethyl acetate in60-80° C. petroleum ether) to give separation of the two isomers. Thefirst higher R_(f) fractions afforded pure title compound as the minorproduct (3.5 g) as an oil.

[0446]¹H NMR (500 MHz, CDCl₃): δ 7.34-7.37 (m, 2H), 7.25-7.31 (m, 3H),5.46 (s, 1H), 4.11-4.17 (m, 2H), 3.63 (s, 2H), 2.70-2.76 (m, 2H), 2.29(tt, J=11.7 and 3.7 Hz, 1 H), 1.75-1.80 (m, 2H), 1.47-1.61 (m, 2H), 1.47(s, 9H).

[0447] MS (ESI): m/z 346 (M+1).

[0448] The lower R_(f) fractions contained phenylacetone and majorproduct 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-2-phenylbutane-1,3-dionefrom which the latter crystallized on standing to give 7 g white solid(m.p. 105-106° C.).

[0449]¹H NMR (360 MHz, CDCl₃): δ 15.23 (s, 1H), 7.3-7.45 (m, 3H),7.15-7.2 (m, 2H), 4-4.1 (m, 2H), 2.35-2.50 (m, 2H), 2.2-2.3 (m, 1H),1.87 (s, 3H), 1.5-1.75 (m, 4H), 1.43 (s, 9H).

[0450] MS (ESI): m/z 346 (M+1).

[0451] Method B:

[0452] Step B1:1-(t-Butoxycarbonyl)piperidine-4-N-methyl-N-methoxycarboxamide

[0453] N-Boc isonipecotic acid (13.56 g, 59.2 mmol), N,O-dimethylhydroxylamine hydrochloride (8.65 g, 88.7 mmol), and1-hydroxybenzotriazole hydrate (15.9 g, 118 mmol) were dissolved in DMF(225 mL) in a 500 mL round-bottom flask and diisopropylethylamine (15.3g, 20.6 mL, 118.3 mmol) was then added with stirring at rt.1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (17.01 g, 88.74 mmol) wasadded in several portions over 10 min with stirring. After 22 h, thereaction mixture was poured into a water and ice mixture (600 mL) andwas extracted with ethyl acetate (5×125 mL). The combined organic layerswere washed with 1N HCl (2×200 mL), 5% sodium bicarbonate (2×200 mL),water and brine, dried over sodium sulfate and concentrated to give thetitle compound (15.58 g) as a yellowish oil.

[0454]¹H NMR (500 MHz, CDCl₃): δ 4.11-4.20 (m, 2H), 3.72 (br s, 3H),3.20 (br s, 3H), 2.75-2.86 (m, 3H), 1.63-1.76 (m, 4H), 1.47 (s, 9H).

[0455] Step B2: 4-Acetyl-1-(t-butoxycarbonyl)piperidine

[0456] After dissolving the Weinreb amide from Step B 1 in anhydrousether (400 mL) under nitrogen and cooling the solution in an ice bath,1.4M methyl magnesium bromide (55 mL) in 3:1 toluene and THF was addedwith stirring and cooling over 30 min. After stirring at 0° C. for 1 h,the reaction was poured into a mixture of ice water (400 mL) and aceticacid (8 mL, 150 mmol). The layers were separated and the aqueous layerwas extracted twice with ether. The combined organic layers were washedwith 0.1N HCl (200 mL), 3% sodium bicarbonate (200 mL), water (200 mL)and brine (200 mL), dried over sodium sulfate, and concentrated to givethe crude product (14.322 g). FC (20-80% ethyl acetate in hexanes) gavethe title compound (9.440 g) as a yellowish oil. R_(f). 0.27 (25% ethylacetate in hexanes). Some starting Weinreb amide was also recovered(3.212 g). R_(f): 0.10 (25% ethyl acetate in hexanes).

[0457]¹H NMR (500 MHz, CDCl₃): δ 4.07-4.14 (m, 2H), 2.75-2.83 (m, 2H),2.46 (tt, J=11.3 and 3.8 Hz, 1H), 2.17 (s, 3H), 1.82-1.87 (m, 2H),1.48-1.57 (m, 2H), 1.46 (s, 9 H).

[0458] Step B3:1-(1-(t-Butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione

[0459] To a suspension of 60% sodium hydride (1.07 g) in THF (15 mL) at0° C. was added a solution of 4-acetyl-1-(t-butoxycarbonyl)piperidinefrom Step B2 (3.03 g, 13.3 mmol) and methyl phenylacetate (6.01 g, 39.9mmol) in THF (6 mL) over 20 min. The reaction was stirred for another 4h as it was allowed to warm to rt. The mixture was diluted with ether(30 mL) and poured into 1N HCl. The layers were separated and theaqueous layer was extracted three times with ether. The combined organiclayers were washed with brine (150 mL), dried over sodium sulfate andconcentrated. The crude product was purified by FC (20% ethyl acetate inhexanes) to give the title compound (3.02 g). R_(f): 0.30 (20% ethylacetate in hexane). The ¹H NMR data was the same as that obtained fromthe product of Method A.

[0460] Step B:4-(5-Benzyl-1-ethyl-(1H)-pyrazol-3-yl)-1-(t-butoxycarbonyl)piperidine(Higher R_(f) Isomer) and4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)-1-(t-butoxycarbonyl)piperidine(Lower R_(f) Isomer)

[0461] Method A:

[0462] 1-(1-(t-Butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dionefrom Step A, from Method A or Method B, Step B3, (0.851 g, 2.46 mmol) inmethanol (25 mL) was added over 10 min to a suspension of ethylhydrazineoxalate (0.444 g, 2.96 mmol) in methanol (5 mL) in a 60° C. oil bath.After 15 h, the reaction was concentrated in vacuo and the residue waspurified by repeated FC using a gradient of 50-100% ethyl acetate inhexanes to give first4-(5-benzyl-1-ethyl-(1H)-pyrazol-3-yl)-1-(t-butoxycarbonyl)piperidine(0.148 g total) as the higher R_(f) product isomer and then the titlecompound (0.373 g total) as the lower R_(f).

[0463] Higher R_(f) Isomer:

[0464]¹H NMR (500 MHz, CDCl₃): δ 7.2-7.3 (m, 2H), 7.3-7.4 (m, 1H), 7.17(d, J=7.5 Hz, 2H), 5.77 (s, 1H), 4.0-4.25 (m, 2H), 3.97 (q, J=7.3 Hz,2H), 3.95 (s, 2H), 2.7-2.9 (m, 2H),2.76(tt, J=11.3 and 3.8 Hz, 1H), 1.92(b rd, J=13 Hz, 1H), 1.5-1.65 (m, 2H), 1.47 (s, 9H), 1.29 (t, J=7.3 Hz,3H).

[0465] Lower R_(f) Isomer:

[0466]¹H NMR (500 MHz, CDCl₃): δ 7.25-7.4 (m, 3H), 7.2 (m, 2H), 5.72 (s,1H), 4.1-4.3 (m, 2H), 4.08 (q, J=7.1 Hz, 2H), 3.95 (s, 2H), 2.7-2.9 (m,2H), 2.66 (tt, J=11.3 and 3.8 Hz, 1H), 1.82 (br d, J=12.8 Hz, 1H),1.4-1.6 (m, 2H), 1.48 (s, 9H), 1.47 (t, J=7.1 Hz, 3H).

[0467] Method B:

[0468] Step B 1: 1-(t-Butoxycarbonyl)4-hydroxymethylpiperidine

[0469] A solution of 25.03 g (109.2 mmole) N-Boc isonipecotic acid wasdissolved in 200 mL THF and treated with 200 mL 1 Mborane-tetrahydrofuran complex in THF, and the mixture was stirredovernight. The mixture was concentrated under vacuum, diluted with 750mL ethyl acetate, and washed with 150 ML 1 N HCl (6×) and then saturatedbrine. The organic layer was dried over sodium sulfate and concentratedto give 24.3 g of crude product as a white solid. This was used as is inthe next step.

[0470]¹H NMR (500 MHz) δ 4.15 (br d, J=13.7 Hz, 2H), 3.52 (d, J=6.2 Hz,2H), 2.69-2.75 (m, 2H), 1.71-1.75 (m, 2H), 1.62-1.70 (m, 1H), 1.47 (s,9H), 1.12-1.21 (m, 2H).

[0471] Step B2: 1-(t-Butoxycarbonyl)-4-formylpiperidine

[0472] A mixture of 17.62 g (135.6 mmole) oxalyl chloride and 250 mLmethylene chloride in a dry ice acetone bath. was treated with asolution of 21.19 g (271.2 mmole) DMSO in 150 mL methylene chloride over20 minutes. After stirring for 20 minutes, a solution of 24.327 g1-(t-butoxycarbonyl)-4-hydroxymethylpiperidine (from Step B1 above) in150 mL methylene chloride was added over 1 h. After an additional 15minutes, 57.17 (565 mmole) triethylamine in 150 mL methylene chloridewas added over half an hour. The reaction mixture was allowed to warn upover night in the cooling bath. The reaction mixture was concentratedunder vacuum to remove about 400 mL methylene chloride, and the residuewas partitioned between 1 L ether and 300 mL water. To this was added200 mL 1 N NaOH, the layers were separated, and the organic layer waswashed with 150 mL 1 N NaOH (2× ), water (3×), and saturated brine,dried over sodium sulfate, and concentrated to give 22.562 g crudeproduct. FC (10˜60% ethyl acetate in hexanes) gave 20.58 g titlecompound as slightly yellowish oil.

[0473] R_(F): 0.29 (3:1 v/v hexanes/ethyl acetate).

[0474]¹H NMR (500 MHz) δ 9.68 (d, J=0.7 Hz, 1H), 3.96˜4.02 (m, 2H),2.92˜2.97 (m, 2H), 2.40˜2.45 (m, 1H), 1.88˜1.94 (m, 2H), 1.53˜1.64 (m,2H), 1.47 (s, 9H).

[0475] Step B3: 1-(t-Butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)piperidine

[0476] A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150mL methylene chloride was added dropwise with stirring to a solution of76.895 g (293.2 mmole) triphenyiphosphine in 150 mL methylene chloridein a 1-L rb flask with ice bath cooling over 1.75 h. After 40 minutes, asolution of 15.631 g (73.29 mmole)1-(t-butoxycarbonyl)-4-formylpiperidine (from Step B2 above) in 100 mLmethylene chloride was added to the resulting brown suspension withstirring and cooling over 40 minutes. After one hour, 200 mL ether and400 mL hexanes was added. The top suspension was filtered throughCelite, and the residue was resuspended in 150 mL methylene chloride andtreated with 300 mL ether. The mixture was filtered, and the solid waswashed with hexanes until the total filtrate was 2 L. The filtrate wasfiltered again through Celite and washed with hexanes. The filtrate waswashed with 100 mL 5% sodium bicarbonate, 300 mL water (2×), and 150 mLbrine. The organic layer was dried over sodium sulfate and concentratedunder vacuum to give 53.5 g crude product as a yellowish solid. Flashchromatography (FC) on 250 g silica gel (0˜15% ethyl acetate in hexanes)gave 21.595 g title compound as a white solid.

[0477] R_(f): 0.57 (15% ethyl acetate in hexanes).

[0478]¹H NMR (500 MHz) δ 6.25 (d, J=8.9 Hz, 1H), 4.04˜4.12 (m, 2H),2.75˜2.83 (m, 2H), 2.42˜2.50 (m, 1H), 1.69˜1.75 (m, 2H), 1.47 (s, 9H),1.29˜1.37 (m, 2H).

[0479] Step B4:1-(t-Butoxycarbonyl)-4-(2-tributylstannylethyn-1-yl)piperidine

[0480] A mixture of 23.199 g (62.85 mmole)1-(t-butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)piperidine (prepared as inStep B3 above) and 600 mL anhydrous THF was cooled with dry ice acetonebath under nitrogen. To this mixture was added 88 mL of a 1.6 M butyllithium solution in hexanes dropwise with stirring and cooling over 50minutes. After one hour, the flask was transferred into an ice bath.After another hour, a solution of 28.64 g (87.99 mmole) tributyltinchloride in 100 mL THF was added with stirring and cooling over 35minutes. After three h, the mixture was concentrated under vacuum toremove some THF, and the residue was partitioned between 600 mL icewater and 800 mL ether. The organic layer was washed with 200 mL ofwater (1×), 2% sodium bicarbonate (1×), water (2×), and saturated brine(1×), dried over sodium sulfate and concentrated under vacuum to give30.104 g crude product as a green-yellowish liquid. FC on 275 g silicagel using cold 2.5˜15% ethyl acetate in hexanes as quickly as possibleto give 27.115 g title compound as a colorless liquid.

[0481] R_(f): 0.45 (10% ethyl acetate in hexanes).

[0482]¹H NMR (500 MHz) δ 3.63˜3.67 (m, 2H), 3.25˜3.30 (m, 2H), 2.64-2.69(m, 1H), 1.74˜1.79 (m, 2H), 1.54˜1.64 (m, 8H), 1.47 (s, 9H), 1.32˜1.39(m, 6H), 0.96˜0.99 (m, 6H), 0.92 (t, J=7.3 Hz, 9H).

[0483] Step B5:4-(1-(t-Butoxycarbonyl)piperidin-4-yl)-1-phenylbutan-2-on-3-yne

[0484] To a mixture of 1.727 g (3.466 mmole)1-(t-butoxycarbonyl)-4-(2-tributyl-stannylethyn-1-yl)piperidine(prepared in Step B4 above) in 18 mL 1,2-dichloroethane was added 0.536g (3.466 mmole) phenylacetyl chloride and 50 mgdichlorobis-(triphenylphosphine)palladium (II). The mixture was refluxedunder nitrogen for 2 h, then concentrated under vacuum. Purification ofthe residue on silica gel (5˜35% ethyl acetate in hexanes) gave 0.784 gtitle compound as a yellow oil.

[0485] R_(f): 0.27 (20% ethyl acetate in hexanes).

[0486]¹H NMR (500 MHz) δ 7.34˜7.38 (m, 2H), 7.28˜7.32 (m, 1H), 7.24˜7.27(m, 2H), 3.82 (s, 2H), 3.49˜3.54 (m, 2H), 3.17˜3.23 (m, 2H), 2.68˜2.73(m, 1H), 1.72˜1.77 (m, 2H), 1.51˜1.57 (m, 2H), 1.47 (s, 9H).

[0487] Tetrakis(triphenylphosphine)palladium gave a similar result.

[0488] Step B6:4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)-1-(tert-butoxycarbonyl)piperidine

[0489] Heating 1.204 g (3.677 mmole)4-(1-(t-butoxycarbonyl)piperidin-4-yl)-1-phenylbutan-2-on-3-yne(prepared in Step B5 above) with 0.662 g (4.413 mmole) ethylhydrazineoxalate and 1.252 g (9.687 mmole) DIEA in 20 mL ethanol over night gavean 8:1 ratio of the title compound and its isomer4-(5-benzyl-1-ethyl-(1H)-pyrazol-3-yl)-1-(tert-butoxycarbonyl)piperidine.Use of ethylhydrazine free base gave even more favorable ratios of thedesired title compound. The desired isomer can be isolated byrecrystallization using hexanes or by silica gel chromatography using5˜10% acetonitrile in methylene chloride in addition to the proceduredescribed in Method A above.

[0490] Step C: 4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidine Di-TFASalt

[0491] To a solution of4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)-1-(t-butoxycarbonyl)piperidinefrom Step B (lower R_(f) isomer) (0.373 g, 1.01 mmol) and anisole (0.219mL, 2.02 mmol) in methylene chloride (15 mL) was added trifluoroaceticacid (1.555 mL, 20.2 mmol). The reaction was stirred at rt for 2.5 h andthen concentrated. The residue was purified on preparative reverse-phaseHPLC using 9.4×250 mm Semi-preparative Zorbax SB-C₁₈ column with17.5-35% acetonitrile gradient in water having 0.5% (v/v) TFA over 15min at 6.05 mL per minute to give the title di-TFA salt compound as anoil. When a mixture of isomers from Step B is used, separation is alsopossible at this step with the above Prep HPLC conditions in which thetitle isomer elutes prior to4-(5-benzyl-1-ethyl-(1H)-pyrazol-3-yl)piperidine.

Procedure 2

[0492]4-(3-Benzyl-(1H)-pyrazol-5-yl)piperidine Di-Trifluoroacetic AcidSalt

[0493] Step A:4-(3-Benzyl-(1H)-pyrazol-5-yl)-1-(t-butoxycarbonyl)piperidine TFA Salt

[0494] A solution of1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenyl-butane-1,3-dione fromProcedure 1, Step A (30 mg, 0.087 mmol), hydrazine di-hydrochloride(10.9 mg, 0.1 mmol) and DIPEA (0.045 mL, 0.25 mmol) in methanol (1 mL)was heated at 50° C. for 16 h. The volatiles were then removed underreduced pressure. Purification of the residue was done on preparativereverse-phase HPLC using a 9.4×250 mm Semi-preparative Zorbax SB-C18column with 35-50% acetonitrile gradient in water having 0.5% (v/v) TFAover 15 min to give the title compound (45.2 mg) as a gel.

[0495] Step B: 4-(3-Benzyl-(1H)-pyrazol-5-yl)piperidine Di-TFA Salt

[0496] To a solution of4-(3-benzyl-(1H-pyrazol-5-yl))-1-(t-butoxycarbonyl)piperidine TFA salt(from Step A) in methylene chloride (1.5 mL) was added anisole (0.017mL) and TFA (0.230 mL). After several h at rt, volatiles were removedunder reduced pressure. Purification of the residue was done bypreparative reverse-phase HPLC using a 9.4×250 mm Semi-preparativeZorbax SB-C18 column with a 15-25% acetonitrile gradient in water having0.5% (v/v) TFA over 15 min at 6.0 mL per minute to give the titlecompound (40.7 mg) as a gel.

Procedure 3

[0497] 4-(4-(2-Phenyleth-1-yl)-1-ethyl-(1H)-pyrazol-5-yl)piperidineDi-TFA Salt

[0498] Step A: 4-Phenylbutyl Bromide

[0499] To a solution of 4-phenyl-1-butanol (21.75 g) in acetonitrile(300 mL) was added triphenylphosphine dibromide (67.23 g) in portionswith stirring over 10 min. After stirring over night under nitrogen,methanol (4 mL) was added and after 1.5 h, the solvent was removed underreduced pressure. Hexanes (200 mL) and ˜75 g silica gel were added tothe residue and the mixture was filtered and the filter cake was elutedwith hexanes. The clear filtrate was concentrated to give 32.8 g ofclear colorless liquid. This product was again eluted through silica gelusing 1.5 L hexanes to give the title compound (24.7 g) as a colorlessliquid.

[0500]¹H NMR (500 MHz, CDCl₃): δ 7.28-7.32 (m, 2H), 7.20-7.23 (m, 3H),3.44 (t, J=6.8 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.93-1.89 (m, 2H),1.77-1.84 (m, 2H).

[0501] Step B: (4-Phenylbut-1-yl)triphenylphosphonium Bromide

[0502] A solution of 4-phenylbutyl bromide from the Step A (24.7 g) andtriphenylphosphine (19.00 g) in toluene (100 mL) was heated at 120-130°C. for 3 days. The reaction was cooled to rt and the solid precipitatewas collected by filtration, washed with toluene and air dried. Thesolid was dissolved in a 2:1 mixture of water and acetonitrile and gavethe title compound (30.6 g) as a white solid after lyopholization.

[0503]¹H NMR (500 MHz, CD₃OD): δ 7.84-7.89 (m, 2H), 7.71-7.81 (m, 15H),7.20-7.23 (m, 1H), 7.11-7.15 (m, 2H), 3.37-3.43 (m, 2H), 2.66 (t, J=7.5Hz, 2H), 1.87 (tt, J=7.5 and 7.3 Hz, 2H), 1.63-1.70 (m, 2H).

[0504] Step C: 1-Benzyl-4-(4-phenylbutylidene)piperidine

[0505] A 0.62M solution of potassium bis(trimethylsilyl)amide in THF(180 mL, 112 mmol) in toluene (250 mL) was added to a mixture of(4-phenylbut-1-yl)triphenylphosphonium bromide from Step B (53 g) intoluene (250 mL) in an ice bath over 15 min with stirring undernitrogen. After stirring for a further 15 min, a solution of1-benzyl-4-piperidone (16.9 g) in toluene (100 mL) was added over 30 minwith stirring. The reaction mixture was allowed to warm to rt over 15 h.The reaction mixture was then poured into cold 1N HCl (400 mL) and thelayers were separated. The organic layer was extracted with two moreportions of 1N HCl. The combined cloudy HCl solution and an oil layer inbetween were washed with toluene (200 mL) before the aqueous layer wasbasified by the addition of potassium hydroxide (30 g). The aqueouslayer was extracted with ether (3×150 mL) and the combined organiclayers were washed with water and brine, dried over sodium sulfate andconcentrated. The crude product was purified by FC (10-15% ethyl acetatein hexanes having 4% (v/v) TEA) to give the title compound (16 g) as acolorless oil.

[0506] R_(f): 0.47 (20% ethyl acetate in hexanes having 4% (v/v) TEA).

[0507]¹H NMR (500 MHz, CDCl₃): δ 7.26-7.38 (m, 7H), 7.18-7.21 (m, 3H),5.18 (t, J=7.4 Hz, 1H), 3.54 (s, 2H), 2.61-2.64 (m, 2H), 2.42-2.49 (m,4H), 2.22-2.27 (m, 4 H), 2.02-2.07 (m, 2H), 1.65-1.71 (m, 2H).

[0508] Step D: 1-(1-Benzylpiperidin-4-yl)-4-phenylbutan-1-one

[0509] To a solution of 4-(4-phenylbutylidene)-1-benzylpiperidine fromStep C (4.37 g) in anhydrous ether (150 mL) under nitrogen with stirringwas add 1M borane solution in THF (45 mL). The reaction was stirred for3 h when water (2 mL) was added dropwise. The mixture was stirred afurther 30 min and was then cooled in an ice bath. A solution of chromicanhydride (2.5 g), concentrated sulfuric acid (5.44 mL) and water (125mL) was added dropwise with vigorous magnetic stirring over 5 min. Afteranother 5 min, the ice bath was removed. After 1.5 h at rt, 0.5N sodiumhydroxide and ether (400 mL each) were added and the mixture was stirreduntil the residue dissolved. The layers were separated and the aqueouslayer was extracted twice with ether. The combined ether layers werewashed with an aqueous EDTA solution, water and brine (100 mL each),dried over sodium sulfate and concentrated under reduced-pressure togive a colorless gel. Flash chromatography on silica gel with 30-50%ethyl acetate in hexanes with 3% (v/v) TEA gave the title compound (1 g)as a colorless gel. R_(f): 0.43 (30% ethyl acetate in hexanes with 3%(v/v) TEA).

[0510]¹H NMR (500 MHz, CDCl₃): δ 7.25-7.33 (m, 7H), 7.16-7.22 (m, 3H),3.51 (s, 2H), 2.89-2.93 (m, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.46 (t, J=7.2Hz, 2H), 2.38 (tt, J=11.5 and 3.9 Hz, 1H), 1.99-2.03 (m, 2H), 1.92 (tt,J=7.2 and 7.6 Hz, 2H), 1.76-1.81 (m, 2H), 1.65-1.72 (m, 2H).

[0511] Step E: 1-(1-Benzylpiperidin-4-yl)-2-formyl-4-phenylbutan-1-one

[0512] To a solution of potassium t-butoxide (0.673 g) in THF (20 mL)under nitrogen and cooled in an ice bath was added a solution of1-(1-benzylpiperidin-4-yl)-4-phenylbutan-1-one from Step D (0.71 g) andmethyl formate (3.76 mL) in THF (12 mL) over 5 minute. The reaction wasstirred for 15 min before being allowed to warm to rt for 2 h. Thereaction was poured into water and extracted with ether (4×100 mL),methylene chloride (100 mL), and THF (100 mL). The combined organiclayers were washed with water and brine, dried over sodium sulfate andconcentrate under reduced pressure. The crude product was purified by FCon silica gel eluting with 5 and 20% methanol in ethyl acetate with 4%TEA to afford the title compound (0.8 g).

[0513]¹H NMR (500 MHz, CDCl₃) showed a 3:1 ratio of enol (δ 8.54 ppm)and aldehyde (δ 9.54 ppm) forms. Other signals from the two forms wereonly partially resolved. The title compound had a retention time of 9.47min on a Zorbax SB-C18 column (4.6×75 mm) eluting with 20-100% gradientof acetonitrile in water with 0.1% TFA over 10 min at 1 mL per min.

[0514] Step F:4-(4-(2-Phenyleth-1-yl)-1-ethyl-(1H)-pyrazol-5-yl)-1-benzylpiperidinedi-TFA Salt

[0515] A solution of1-(1-benzylpiperidin-4-yl)-2-formyl-4-phenyl-1-butanone from Step E(76.5 mg) and ethylhydrazine oxalate (45 mg) in methanol (4 mL) washeated at 45° C. for 15.5 h. The solvent was removed under reducedpressure. The residue was purified by preparative reverse-phase IHPLCusing a 9.4×250 mm Semi-preparative Zorbax SB-C18 column with 30-50%acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 7.1mL per min to give the title compound (45 mg) as the faster-eluting,minor isomer.

[0516]¹H NMR (500 MHz, CD₃OD): δ 7.46-7.52 (m, 5H), 7.37 (s, 1H),7.21-7.24 (m, 2 H), 7.12-7.15 (m, 3H), 4.32 (s, 2H), 4.17 (q, J=7.2 Hz,2H), 3.53 (br d, J=12.4 Hz, 2H), 3.06-3.12 (m, 3H), 2.79-2.88 (m, 4H),2.10-2.20 (m, 2H), 1.78 (br d, J=14.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H).The isomeric assignment was confirmed by a NOESY spectrum.

[0517] HPLC/MS (ESI): m/z 374.3 (M+1), 2.51 min.

[0518] Step G:4-(4-(2-Phenyleth-1-yl)-1-ethyl-(1H)-pyrazol-5-yl)piperidine Di-TFA Salt

[0519] A mixture of ammonium formate (119 mg), 20% Pd(OH)₂/C (5 mg) and4-(4-(2-phenylethyl)-1-ethyl-(1H-pyrazol-5-yl))-1-benzylpiperidinedi-TFA salt from Step F in methanol (2 mL) was heated at 60° C. for 1.5h. The solvent was removed under reduced pressure and the residue waspurified by preparative reverse-phase HPLC using a 9.4×250 mmSemi-preparative Zorbax SB-C18 column with 20-35% acetonitrile gradientin water having 0.5% (v/v) TFA over 15 min at 6.25 mL per min to givethe title compound as the di-TFA salt (25 mg) as a gel.

[0520]¹H NMR (500 MHz, CD₃OD): δ 7.40 (s, 1H), 7.22-7.25 (m, 2H),7.13-7.17 (m, 3 H), 4.20 (q, J=7.3 Hz, 2H), 3.42-3.46 (m, 2H), 3.05-3.15(m, 3H), 2.83-2.90 (m, 4 H), 2.04-2.14 (m, 2H), 1.74-1.79 (m, 2H), 1.36(t, J=7.4 Hz, 3H). The isomer assignment was confirmed by an NOEdifference spectrum.

Procedure 4A

[0521] 4-(3-(4-Fluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidine Di-TFA

[0522] The title compound was prepared using essentially the sameprocedure as that described in Procedure 1, but substituting methyl4-fluorophenylacetate for methyl phenylacetate in Step A, Method B, StepB3.

Procedure 4B

[0523] 4-(3-(3,4-Difluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidineDi-TFA

[0524] The title compound was prepared using essentially the sameprocedure as that described in Procedure 1, but substituting methyl3,4-difluorophenylacetate for methyl phenylacetate in Step A, Method B.

Procedure 5

[0525] 4-(3-(Benzofurazan-4-yl)prop-1-yl)piperidine Hydrochloride

[0526] Step A: (1-t-Butoxycarbonylpiperidin4-yl)acetaldehyde

[0527] A solution of oxalyl chloride (1.23 mL, 14.1 mmol) in methylenechloride (50 mL) was cooled to −78° C. DMSO (2.0 mL, 28.3 mmol), wasadded slowly via syringe. After 10 min,4-(2-hydroxyeth-1-yl)-1-t-butoxycarbonylpiperidine (2.7 g, 11.8 mmol) inmethylene chloride (15 mL) was added. The cold mixture was stirred foran additional 20 min then TEA (8.2 mL, 59 mmol) was added. The mixturewas warmed to rt and stirred for 1.5 h, then diluted with methylenechloride (300 mL). The organic phase was washed with 1M sodiumhydroxide, dried over sodium sulfate and concentrated. FC (125 g silica,2.5/1 hexanes/ethyl acetate) afforded the title compound (2.25 g).

[0528]¹H NMR (300 MHz, CDCl₃): δ 1.1-1.2 (m, 2H), 1.45 (s, 9H),1.65-1.75 (m, 2H), 1.99-2.13 (m, 1H), 2.38-2.4 (d, 2H), 2.65-2.8 (m,2H), 4.03-4.15 (m, 2H), 9.78 (s, 1 H)

[0529] Step B: 4-(Prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine

[0530] A solution of methyltriphenylphosphonium bromide (5.3 g, 14.8mmol) in THF (50 mL) was cooled to 0° C. under nitrogen. Potassiumhexamethyl disilazide (27.7 mL, 0.5M toluene solution, 13.9 mmol) wasadded and the mixture was stirred for 30 min. A solution of(1-t-butoxycarbonylpiperidin-4-yl)acetaldehyde from Step A (2.25 g, 9.9mmol) in THF (10 mL) was added and the mixture was warmed to rt. After30 min, the reaction was complete by tlc analysis. The mixture wasdiluted with ethyl acetate (200 mL) and washed with water and brine (100mL each). The organic phase was dried over sodium sulfate andconcentrated to give an oil which was purified by FC (75 g silica, 10/1hexane/ethyl acetate) to afford the title compound (1.61 g).

[0531]¹H NMR (300 MHz, CDCl₃): δ 1.03-1.18 (m, 2H), 1.45 (s, 9H),1.4-1.5 (m, 1H), 1.6-1.7 (m, 2H), 1.99-2.13 (t, 1H), 2.62-2.75 (m, 2H),4.03-4.15 (m, 2H), 4.98-5.12 (m, 2H), 5.7-5.83 (m, 1H).

[0532] Step C: 4-Bromobenzofurazan

[0533] To a solution of 2,6-dibromoaniline (10 g, 40 mmol) in glacialacetic acid (160 mL) was added 30% hydrogen peroxide (30 mL). Themixture was left for 48 h at which point crystals had precipitated. Thecrystals were collected by filtration, washed with acetic acid and waterthen dried under high vacuum to give 2,6-dibromonitrosobenzene (6.24 g).This material (2.6 g, 10 mmol) was dissolved in DMSO (25 mL) along withsodium azide (650 mg, 10 mmol). The mixture was heated to 100° C. for 1h then cooled to rt and diluted with ethyl acetate and water. The layerswere separated and the organic phase was washed with water and brine,then dried over sodium sulfate and concentrated. FC (75 g silica, 10/1hexane/ethyl acetate) afforded the title compound (1.7 g).

[0534]¹H NMR (300 MHz, CDCl₃): δ 7.25-7.35 (dd, 1H), 7.6-7.65 (d, 1H),7.78-7.82 (d, 1H)

[0535] Step D: 4-(3-(Benzofurazan-4-yl)prop-1-yl)piperidineHydrochloride

[0536] A solution of 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidinefrom Step B (330 mg, 1.46 mmol) in dry THF (0.5 mL) was cooled to 0° C.and a solution of 9-BBN (3.2 mL, 0.5 M in THF, 1.61 mmol) was added. Themixture was warmed to rt and stirred for 5 h. Potassium carbonate (405mg, 2.93 mmol), 1,2-bis(diphenylphosphino)-ferrocenyl palladiumdichloride (60 mg, 0.073 mmol) and 4-bromobenzofurazan (from Step C)(292 mg, 1.46 mmol) were added followed by dry DMF (5 mL). The resultingmixture was heated to 55° C. overnight then diluted with ethyl acetate.The solution was washed with water (3×) and brine, then dried oversodium sulfate and concentrated. FC (15 g silica, 5/1 hexane/ethylacetate) afforded the title Boc derivative. Heating in 1% conc.HCl/methanol at 50° C. for 2 h followed by removal of solvent and dryingunder vacuum afforded the title compound as the hydrochloride (155 mg).

[0537]¹H NMR (300 MHz, CD₃OD): δ 1.31-1.42 (m, 4H), 1.6-1.75 (m, 1H),1.84-2.0 (m, 4H), 2.9-3.1 (m, 4H), 3.3-3.4 (m, 2H), 7.25-7.3 (d, 1H),7.4-7.5 (dd, 1H), 7.7-7.75 (d, 1H).

Procedure 6

[0538] 4-(3-(Benzofurazan-5-yl)prop-1-yl)piperidine Hydrochloride

[0539] Using essentially the same methods as in Procedure 5, butsubstituting 2,5-dibromoaniline for 2,6-dibromoaniline in Step C, thetitle compound was prepared.

Procedure 7

[0540] 4-(3-(4-Cyanophenyl)prop-1-yl)piperidine Hydrochloride

[0541] Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidinefrom Procedure 5, Step B (475 mg, 2.1 mmol) and using essentially thesame methods as in Procedure 5, Step D, but substituting4-bromobenzonitrile (382 mg, 2.1 mmol), the title compound (337 mg) wasobtained as the hydrochloride.

[0542]¹H NMR (300 MHz, CD₃OD). δ 1.31-1.42 (m, 4H), 1.58-1.75 (m, 5H),1.9-2.1 (m, 2H), 2.67-2.77 (t, 2H), 2.9-3.0 (m, 2H), 3.3-3.4 (m, 2H),7.35-7.4 (d, 2H), 7.6-7.63 (d, 2H).

Procedure 8

[0543] 4-(3-(4-Cyano-3-fluorophenyl)prop-1-yl)piperidine Hydrochloride

[0544] Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidinefrom Procedure 5, Step B and using essentially the same methods as inProcedure 5, Step D, but substituting 4-bromo-2-fluorobenzonitrile, thetitle compound was obtained as the hydrochloride.

Procedure 9

[0545] 4-(3-(4-Fluorophenyl)prop-1-yl)piperidine Hydrochloride

[0546] Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine(from Procedure 5, Step B) and using essentially the same methods as inProcedure 5, Step D, but substituting 4-bromofluorobenzene, the titlecompound was obtained as the hydrochloride.

Procedure 10

[0547] 4-(3-(Quinolin-3-yl)propyl)piperidine Di-Hydrochloride Salt

[0548] Step A:1-(t-Butoxycarbonyl)-4-(3-(quinolin-3-yl)propyl)piperidine

[0549] A solution of 1-(t-butoxycarbonyl)-4-(prop-2-en-1-yl)piperidine(from Procedure 5, Step B) (260 mg, 1.15 mmol) in THF (3 mL) under argonwas treated with 0.5M 9-BBN solution in THF (2.30 mL, 1.15 mmol). Theresulting mixture was stirred at rt for 2 h, then treated with sodiummethoxide (68 mg, 1.25 mmol). The resulting mixture was stirred until itwas homogeneous (˜15 min) and then was treated with 3-(bromo) quinoline(0.155 mL, 1.15 mmol) and[1,1′-bis(triphenylphosphino)ferrocene)dichloropalladium.methylenechloride (41 mg, 0.05 mmol). The resulting mixture was heated at refluxfor 30 min, cooled and quenched with IN NaOH (20 mL). The quenchedreaction was extracted with 2×50 mL of ether; the extracts were driedover magnesium sulfate, combined and concentrated. FC (15 g of silicagel, 4:1 v/v hexanes/ethyl acetate) afforded the title compound (240mg).

[0550]¹H NMR (300 MHz, CDCl₃): δ 1.00-1.16 (m, 2H), 1.25-1.40 (m, 2H),1.45 (s, 9H), 1.60-1.80 (m, 5H), 2.62-2.72 (m, 2H), 2.79 (t, J=7.8, 2H),4.06 (br s, 2H), 7.52 (m, 1H), 7.66 (m, 1H), 7.76 (dd, J=8.0, 1.6, 1H),7.91 (d, J=1.6, 1H), 8.77 (d, J=2.2, 1H).

[0551] Step B: 4-(3-(Quinolin-3-yl)propyl)piperidine Di-HydrochlorideSalt

[0552] A solution of1-(t-butoxycarbonyl)-4-(3-(quinolin-3-yl)propyl)piperidine from Step A(240 mg, 0.68 mmol) in 1M HCl solution (8 mL) in methanol was stirred atrt for 48 h. The solution was concentrated and the residue crystallizedfrom ethyl acetate to afford the title compound (182 mg),

[0553]¹H NMR (500 MHz, CD₃OD): δ 1.37-1.49 (m, 4H), 1.67-1.74 (m, 2H),1.85-1.91 (m, 2H), 1.99 (app d, J=13.5 Hz, 2H), 2.99 (app t, J=11.5 Hz,2H), 3.05 (t, J=8.0 Hz, 2H), 3.38 (app d, J=12.5 Hz, 1H), 7.97 (t, J=7.0Hz, 1H), 8.13 (dt. J=1.0 and 7.0 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.31(d, J=8.0 Hz, 1H), 9.10 (s, 1H), 9.21 (d, J=1.0 Hz, 1H).

Procedure 11

[0554]4-(3-(2-Pyridyl)propyl)piperidine Di-TFA Salt

[0555] Step A: 1-(t-Butoxycarbonyl)-4-(3-(2-pyridyl)propyl)piperidine

[0556] The title compound was prepared using a procedure analogous tothat described in Procedure 10, Step A, substituting (2-bromo)pyridinefor (3-bromo)quinoline. FC (4:1 v/v hexanes/ethyl acetate followed by3:2 v/v hexanes/ethyl acetate) provided the title compound (135 mg,48%).

[0557]¹H NMR (500 MHz, CDCl₃): δ 1.05-1.81 (m, 10H), 1.46 (s, 9H),2.67-2.82 (m, 2 H), 3.65 (m, 1H), 4.08-4.16 (m, 2H), 7.14-7.18 (m, 2H),7.63 (m, 1H), 8.54 (d, J=4.4 Hz, 1H).

[0558] HPLC/MS (ESI): m/z 304 (M+1).

[0559] Step B: 4-(3-(2-Pyridyl)propyl)piperidine Di-TFA Salt

[0560] To a solution of1-(t-butoxycarbonyl)-4-(3-(2-pyridyl)propyl)piperidine (from Step A)(128 mg, 0.42 mmol) in methylene chloride (1 mL) was added TFA (1 mL).After stirring for 2 h at rt, the reaction was concentrated to give thetitle compound (36 mg).

[0561]¹H NMR (500 MHz, CDCl₃): δ 1.22-1.46 (m, 5H), 1.73-1.79 (m, 4H),2.68 (t, J=11.8 Hz, 2H), 2.78 (t, J=7.8 Hz, 2H), 3.19 (d, J=11.8 Hz,2H), 5.32 (br s, 1H), 7.09-7.15 (m, 2H), 7.59 (t, J 7.7 Hz, 2H), 8.52(d, J=4.6 Hz, 1H).

Procedure 12

[0562] 4-(3-(4-(Trifluoromethyl)pyrimidin-2-yl)propyl)piperidine

[0563] Step A:1-(t-Butoxycarbonyl)-4-(3,3-dibromoprop-2-en-1-yl)piperidine

[0564] To a solution of carbon tetrabromide (286 mg, 0.86 mmol) inmethylene chloride (4 mL) at −10° C. was added triphenylphosphine (339mg, 1.29 mmol). After 10 min, a solution of((1-t-butoxycarbonyl)piperidin-4-yl)acetaldehyde (from Procedure 5, StepA) (98 mg, 0.43 mmol) and TEA (0.060 mL, 0.43 mmol) in methylenechloride (2 mL) was added. After stirring at rt for 2 h, the reactionmixture was concentrated. The residue was purified by FC (9:1 v/vhexanes/ethyl acetate followed by 1:1 v/v hexanes/ethyl acetate) to givethe title compound (118 mg).

[0565]¹H NMR (500 MHz, CDCl₃): δ 1.14-1.22 (m, 2H), 1.47 (s, 9H),1.57-1.60 (m, 1H), 1.67 (br d, J=12.6 Hz, 2H), 2.08 (t, J=7.1 Hz, 2H),2.70 (t, J=12.7 Hz, 2H), 4.10 (br d, J=12.6 Hz, 2H), 6.42 (t, J=7.4 Hz,1H).

[0566] Step B: 1-(t-Butoxycarbonyl)-4-(prop-2-yn-1-yl)piperidine

[0567] To a solution of 118 mg (0.31 mmol) of1-(t-butoxycarbonyl)-4-(3,3-dibromoprop-2-en-1-yl)piperidine from Step Ain THF (4 mL) at −78° C. was added a 2.5M solution of n-butyl lithium(0.370 mL, 0.92 mmol). After stirring at −78° C. for 45 min, thereaction mixture was quenched with sat'd ammonium chloride (4 mL) anddiluted with ether (25 mL). After separating the phases, the aqueouslayer was extracted with ether. The combined organic phases were washedwith brine, dried over magnesium sulfate and concentrated. The residuewas purified by FC (4:1 v/v hexanes/ether) to give the title compound(55 mg).

[0568]¹H NMR (500 MHz, CDCl₃): δ 1.18-1.26 (m, 2H), 1.47 (s, 9H),1.60-1.67 (m, 1H), 1.77 (br d, J=13.2 Hz, 2H), 1.99 (t, J=2.6 Hz, 1H),2.16 (dd, J=6.6 Hz, 2.5, 2H), 2.68-2.74 (m, 2H), 4.12 (br d, J=13.0 Hz,2H).

[0569] Step C:1-(t-Butoxycarbonyl)-4-(3-((4-trifluoromethyl)pyrimidin-2-yl)prop-2-yn-1-yl)piperidine

[0570] To a solution of1-(t-butoxycarbonyl)-4-(prop-2-yn-1-yl)piperidine from Step B (86 mg,0.39 mmol) in TEA (4 mL) under argon at 0° C. was added2-chloro-4-(trifluoromethyl)pyrimidine (0.070 mL, 0.58 mmol). Afterstirring at 0° C. for 5 min,dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol), andcopper iodide (4 mg, 0.02 mmol) was added and the reaction vessel wasflushed with argon. After 3 h at 60° C., the reaction mixture was cooledto rt and quenched with 1N sodium hydroxide (5 mL) and diluted withether (25 mL). After separating the phases, the aqueous layer wasextracted again with ether. The combined organic phases were washed withbrine, dried over magnesium sulfate and concentrated. The residue waspurified by FC (9:1 v/v hexanes/ethyl acetate followed by 2:1 v/vhexanes/ethyl acetate) to give the title compound (132 mg).

[0571]¹H NMR (400 MHz, CDCl₃): δ 1.26-1.33 (m, 2H), 1.46 (s, 9H),1.80-1.88 (m, 3H), 2.46 (d, J=6.4 Hz, 2H), 1.99 (br t, J=11.2 Hz, 1H),4.10-4.40 (m, 2H), 7.54 (d, J=5.0 Hz, 1H), 8.94 (d, J=5.0 Hz, 1H).

[0572] Step D:1-(t-Butoxycarbonyl)-4-(3-((4-trifluoromethyl)pyrimidin-2-yl)prop-1-yl)piperidine

[0573] To a solution of1-(t-butoxycarbonyl)-4-(3-((4-trifluoromethyl)pyrimidin-2-yl)prop-2-yn-1-yl)piperidinefrom Step C (130 mg) in methanol (4 mL) was added 10% palladium oncarbon (15 mg). The mixture was hydrogenated using a Parr shaker set at40 psi. After TLC indicated the absence of the starting material, thereaction was filtered through a 0.45 micron nylon membrane polypropylenefilter and concentrated. FC (9:1 v/v hexanes/ethyl acetate followed by2:1 v/v hexanes/ethyl acetate) of the residue afforded the titlecompound.

[0574]¹H NMR (400 MHz, CDCl₃): δ 1.04-1.15 (m, 2H), 1.27-1.49 (m, 3H),1.46 (s, 9H), 1.68 (br d, J=12.7 Hz, 2H), 1.85-1.93 (m, 2H), 2.68 (br t,J=12.1 Hz, 2H), 3.05 (t, J=7.7 Hz, 2H), 4.08(br d, J=11.5 Hz, 2H),7.47(d, J=5.0 Hz, 1H), 8.92 (d, J=5.0 Hz, 1H).

[0575] Step E:4-(3-((4-Trifluoromethyl)pyrimidin-2-yl)prop-1-yl)piperidine

[0576] The title compound was prepared from1-(t-butoxycarbonyl)-4-(3-((4-trifluoromethyl)pyrimidin-2-yl)prop-1-yl)piperidine(from Step D) (17 mg, 0.046 mmol) using a procedure analogous to thatdescribed in Procedure 10, Step B. FC (95:5:0.5 v/v/v methylenechloride/methanol/NH₄OH) afforded the title compound (22 mg).

[0577]¹H NMR (300 MHz, CDCl₃): δ 1.21-3.45 (m, 15H), 7.52 (d, J=5.0 Hz,1H), 8.95 (d, J=5.0 Hz, 1H).

Procedure 13

[0578] 4-(N-(Pyrimidin-2-yl)-N-(prop-1-yl)amino)piperidineDi-Hydrochloride Salt

[0579] Step A: 4-Amino-1-t-butoxycarbonylpiperidine

[0580] 1-t-Butoxycarbonylpiperidin-4-one (20 g, 100 mmol), benzylamine(11 mL, 100 mmol) and sodium triacetoxyborohydride (32 g, 150 mmol) werestirred together in 1,2-dichloroethane (400 mL) for 3 h. The resultingmixture was diluted with ethyl acetate (1 L) and washed with 1M aqueoussodium hydroxide (500 mL) followed by brine (500 mL). The organic phasewas dried over sodium sulfate and concentrated to afford4-N-benzylamino-1-t-butoxycarbonyl piperidine (30.1 g) as a viscous oil.The oil was dissolved in methanol (400 mL) and ammonium formate (39 g,600 mmol) was added. The vessel was purged with nitrogen and 10%palladium-on carbon (6.5 g, 6 mmol) was added. The mixture was refluxedfor 1 h and then filtered through celite and concentrated. Drying undervacuum afforded the title compound (20 g).

[0581]¹H NMR (300 MHz, CDCl₃): δ 1.15-1.3 (m, 2H), 1.43 (s, 9H), 1.7-1.9(m, 4H), 2.65-2.72 (m, 3H), 3.95-4.1 (m, 2H).

[0582] Step B: 4-(N-(Pyrimidin-2-yl)amino)-1-t-butoxycarbonylpiperidine

[0583] 4-Amino-1-t-butoxycarbonylpiperidine from Step A, (1.9 g, 9.5mmol), 2-chloropyrimidine (1.1 g, 9.5 mmol) and DIPEA (3.3 mL, 19 mmol)were combined in isopropanol (10 mL) and the mixture was refluxed for 24h. The mixture was cooled, diluted with methylene chloride (100 mL) andwashed with water and brine. The organic phase was dried over sodiumsulfate and concentrated. FC (60 g silica, 1/1 hexanes/ethyl acetate)afforded the title compound (0.97 g).

[0584]¹H NMR (300 MHz, CDCl₃): δ 1.31-1.45 (m, 2H), 1.44 (s, 9H),2.0-2.1 (m, 2H), 2.9-3.0 (m, 2H), 3.9-4.1 (m, 3H), 5.0-5.05 (m, 1H),6.5-6.58, (t, 1H), 8.15-8.2 (d, 2 H).

[0585] Step C:4-(N-(Pyrimidin-2-yl)-N-(allyl)amino)-1-t-butoxycarbonyl-piperidine

[0586] A solution of4-(N-(pyrimidin-2-yl)amino)-1-t-butoxycarbonylpiperidine from Step B(528 mg, 1.9 mmol) in dry THF (5 mL) was cooled to −78° C. and asolution of sodium hexamethyldisilazide (2.8 mL, 1.0 M in THF, 2.8 mmol)was added via syringe. The mixture was stirred cold for 20 min thenallyl bromide (0.23 mL, 2.7 mmol) was added. The mixture was then warmedto rt and stirred for 1.5 h at which time TLC showed very littlestarting material. The solution was poured into sat'd ammonium chlorideand methylene chloride. The layers were separated and the organic phasewas dried over sodium sulfate and concentrated. FC (25 g silica, 4/1hexanes/ethyl acetate) afforded the title compound (367 mg).

[0587]¹H NMR (300 MHz, CDCl₃): δ 1.45 (s, 9H), 1.6-1.8 (m, 4H),2.75-2.85 (m, 2H), 4.1-4.3 (m, 4H), 4.74.8 (m, 1H), 5.05-5.17 (m, 2H),5.92-5.98 (m, 1H), 6.45-6.5 (t, 1H), 8.3-8.35 (d, 2H).

[0588] Step D: 4-(N-(Pyrimidin-2-yl)-N-(prop-1-yl)amino)piperidineDi-Hydrochloride Salt

[0589] In a round bottom flask purged with nitrogen4-(N-(pyrimidin-2-yl)-4-N-(allyl)amino)-1-t-butoxylcarbonylpiperidinefrom Step C (461 mg, 1.45 mmol) was dissolved in methanol (4 mL) and 10%palladium on carbon (150 mg, 0.14 mmol) was added. The mixture wasstirred under 1 atm of hydrogen using a balloon for 1.5 h. The mixturewas filtered through celite and concentrated. FC (20 g silica, 3/1hexanes/ethyl acetate) afforded4-(N-(pyrimidin-2-yl)4-N-(prop-1-yl)amino)-1-t-butoxylcarbonylpiperidine.

[0590]¹H NMR (400 MHz, CDCl₃). δ 0.9-1.0 (t, 3H, J=7 Hz), 1.5 (s, 9H),1.6-1.8 (m, 6 H), 2.8-2.9 (m, 2H), 3.33-3.4 (m, 2H), 4.2-4.27 (m, 2H),4.7-4.8 (m, 1H), 6.42-6.45 (t, 1H), ), 8.3-8.35 (d, 2H).

[0591] This material was dissolved in 2% conc. HCl/methanol and heatedto 50° C. for 2 h. Removal of solvent and drying under vacuum affordedthe title compound as a white solid.

Procedure 14

[0592] 4-(3-(3,4-Difluorophenyl)prop-1-yl)piperidine Hydrochloride Salt

[0593] Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidinefrom Procedure 5, Step B and using essentially the same methods as inProcedure 5, Step D, but substituting 3,4-difluorobromobenzene, thetitle compound was obtained as the hydrochloride.

Procedure 15

[0594] 4-(5-Benzyl-1-(prop-1-yl)-(1H)-pyrazol-3-yl)piperidineDi-Hydrochloride SSalt (Higher R_(f) Isomer) and4-(3-benzyl-1-(prop-1-yl)-(1H)-pyrazol-5-yl)piperidine Di-HydrochlorideSalt (Lower R_(f) Isomer)

[0595] Using essentially the same methods as in Procedure 1, Step B-C,but substituting propylhydrazine for ethylhydrazine in Step B, the titlecompounds were prepared.

Procedure 16

[0596] 4-(3,3-Difluoro-3-phenylprop-1-yl)piperidine

[0597] Step A:1-(Benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-en-1-yl)piperidine

[0598] DIPEA (4.6 mL, 3.4 g, 26 mmol) was added to a solution of4-(hydroxymethyl)piperidine (2.00 g, 17.4 mmol) dissolved in methylenechloride (20 mL). The solution was cooled in an ice bath and benzylchloroformate (2.5 mL, 3.0 g, 18 mmol) was added dropwise over 10 min.After warming to rt and stirring for 96 h, the mixture was diluted withethyl acetate (50 mL) and washed in succession with 25 mL each ofsaturated aq. sodium bicarbonate, 2N aq. HCl, saturated aq. sodiumbicarbonate, and saturated aq. brine. The organic layer was dried(sodium sulfate), decanted, and evaporated to give 4.14 g of1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine.

[0599] 1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (1.92 g,4.53 mmol) was added to a solution of1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine (1.00 g, 4.01 mmol) inmethylene chloride (20 mL) and the mixture was stirred at rt for 45 min.Ether (75 mL) and 1.3 N aq. NaOH (25 mL) were added and stirring wascontinued for 15 min. The mixture was transferred to a separatory funnelwith additional ether (30 mL) and 1.3 N aq. NaOH (20 mL). The organiclayer was separated, washed with saturated aq. brine (20 mL), dried(sodium sulfate), decanted, and evaporated to give 846 mg of1-(benzyloxycarbonyl)4-piperidine carboxaldehyde as a colorless syrup.

[0600] Diethyl (2-oxo-2-phenylethyl)phosphonate (0.96 mL, 1.1 g, 4.4mmol) was added in one portion to a stirred suspension of sodium hydride(60% oil dispersion, 158 mg, 3.95 mmol) in THF (20 mL). After 15 min. atrt, the clear solution was cooled in an ice bath and1-(benzyloxycarbonyl)-4-piperidinecarboxaldehyde (840 mg, 3.40 mmol) wasadded in THF (1.0 mL) with additional THF (2×1.0 mL) for rinsing.Stirring was continued for a total of 2 h, with slow warming to rt. Themixture was then partitioned between ether (120 mL) and 2.5 N aq. NaOH(60 mL). The organic layer was washed with saturated aq. brine (60 mL),dried (sodium sulfate), decanted, and evaporated. The crude product waspurified by FC, eluting with 15-20% ethyl acetate in hexane, to give0.95 g of the title compound as a colorless syrup.

[0601]¹H NMR (400 MHz, CDCl₃): δ 7.82 (d, J=8 Hz, 2H), 7.57 (t, J=8 Hz,1H), 7.48 (t, J=8 Hz, 2H), 7.39-7.29 (m, 5H), 6.99 (dd, J=15, 6 Hz, 1H),6.87 (dd, J=15 and 1 Hz, 1H), 5.15 (s, 2H), 2.97-2.82 (m, 2H), 2.50-2.39(m, 1H), 1.89-1.77 (m, 2 H), 1.54-1.39 (m, 2H).

[0602] MS (ESI): m/z 367 (M+NH₃+H).

[0603] Step B:2-(2-(1-(Benzyloxycarbonyl)piperidin-4-yl)ethyl)-2-phenyl-1,3-dithiolane

[0604] 1-(Benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-en-1-yl)piperidinefrom Step A (0.95 g, 2.7 mmol) was hydrogenated using 5% Pd/C (10 mg) in95% ethanol (20 mL) at atmospheric pressure. After 3.5 h, the mixturewas filtered and the catalyst was washed with 95% ethanol. Evaporationof the filtrate gave 0.95 g of1-(benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-yl)piperidine as acolorless syrup.

[0605] Boron trifluoride-acetic acid complex (BF₃.2-CH₃CO₂H, 0.370 mL,501 mg, 2.67 mmol) was added to a solution of 1,2-ethanedithiol (0.440mL, 494 mg, 5.25 mmol) and(1-(benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-yl)piperidine (930 mg,2.65 mmol) in methylene chloride (4.0 mL) at rt. After 6 h, the mixturewas diluted with ether (50 mL) and washed with saturated aq. sodiumbicarbonate (2×25 mL), 2.5 N aq. NaOH (25 mL), and saturated aq. brine(25 mL). The organic layer was dried (sodium sulfate), decanted, andevaporated. The crude product was purified by FC, eluting with 10% ethylacetate in hexane, to give 1.05 g of the title compound as a colorlessliquid.

[0606]¹H NMR (400 MHz, CDCl₃): δ 7.66 (d, J=8 Hz, 2H), 7.38-7.26 (m,7H), 7.22 (t, J=8 Hz, 1H), 5.10 (s, 2H), 4.18-4.02 (m, 2H), 3.41-3.32(m, 2H), 3.29-3.20 (m, 2H), 2.79-2.62 (m, 2H), 2.40-2.32 (m, 2H),1.65-1.54 (m, 2H), 1.40-1.27 (m, 1H), 1.24-1.16 (m, 2H), 1.10-0.97 (m,2H);

[0607] HPLC/MS (ESI): m/z 428 (M+H); HPLC: 4.21 min.

[0608] Step C:1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-phenylprop-1-yl)piperidine

[0609] 1,3-Dibromo-5,5-dimethylhydantoin (74 mg, 0.26 mmol) was stirredwith methylene chloride (0.50 mL) at rt, and the suspension was thencooled in a dry ice/isopropanol bath. After 5 min., hydrogenfluoride.pyridine (70% HF, 0.18 mL) was added over 1 min. After 5 min.,a solution of2-(2-(1-(benzyloxycarbonyl)piperidin-4-yl)ethyl)-2-phenyl-1,3-dithiolanefrom Step B (100 mg, 0.234 mmol) in methylene chloride (0.20 mL) wasadded over 1 min. After 10 min, the reaction mixture was diluted intomethylene chloride (25 mL) and washed with water (10 mL) containingsodium bisulfite (0.5 g). The organic layer was washed with saturatedaq. sodium bicarbonate (2×10 mL) followed by saturated aq. brine (10mL), dried (sodium sulfate), decanted, and evaporated to give 98 mg ofcolorless syrup. This material was combined with 195 mg of crude productfrom two similar reactions and purified by FC, eluting with 8% ethylacetate in hexane, to give 247 mg of1-(benzyloxycarbonyl)-4-(3,3-difluoro-3-phenylprop-1-yl)piperidine (Rf:0.3 using 10% ethyl acetate in hexane) containing some residualimpurity.

[0610] The partially purified1-(benzyloxycarbonyl)-4-(3,3-difluoro-3-phenylprop-1-yl)piperidine (247mg) was hydrogenated at atmospheric pressure in 95% ethanol (4.0 mL)containing 20% Pd(OH)₂/C (60 mg). After 6 h, additional 20% Pd(OH)₂/C(32 mg) was added and the hydrogenation was continued for another 16 h.The mixture was filtered and the catalyst was washed with 95% ethanol.Evaporation of the filtrate gave 164 mg of crude4-(3,3-difluoro-3-phenylprop-1-yl)piperidine as a colorless syrup.

[0611] Di-t-butyl dicarbonate (178 mg, 0.816 mmol) was transferred withmethylene chloride (2×0.5 mL) to a solution of crude4-(3,3-difluoro-3-phenylprop-1-yl)piperidine (164 mg) in methylenechloride (2.0 mL). After stirring at rt for 1 h, the solution was storedat −20° C. for 48 h. The mixture was then diluted into ethyl acetate (25mL) and washed with saturated aqueous sodium bicarbonate (10 mL)followed by saturated aqueous brine (10 mL). The organic layer was dried(sodium sulfate), decanted, and evaporated. The crude product waspurified by FC, eluting with 4-5% ethyl acetate in hexane to give thetitle compound as 112 mg of colorless syrup. R_(f): 0.25 (5% ethylacetate in hexane).

[0612]¹H NMR (400 MHz, CDCl₃): δ 7.50-7.40 (m, 5H), 4.24-3.99 (m, 2H),2.64 (bt, J=12 Hz, 2H), 2.14 (tm, J=16 Hz, 2H), 1.62 (bd, J=12 Hz, 2H),1.45 (s, 9H), 1.42-1.33 (m, 3H), 1.13-1.00 (m, 2H).

[0613] Step D: 4-(3,3-Difluoro-3-phenylprop-1-yl)piperidine

[0614] Trifluoroacetic acid (2.5 mL, 3.7 g, 32 mmol) was added dropwiseto a solution of1-(t-butoxycarbonyl)4-(3,3-difluoro-3-phenylprop-1-yl)piperidine fromStep C (42 mg, 0.12 mmol) in methylene chloride (2.5 mL) at 0° C. After80 min., the solution was transferred using a double-ended needle to arapidly stirred solution of sodium bicarbonate (5.0 g, 60 mmol) in water(50 mL). Ether (50 mL) and 2.5 N aq. NaOH (20 mL) were added, followedby solid brine to saturate the aqueous layer. The aqueous layer wasseparated and extracted with ether (50 mL). The organic layers werewashed in succession with saturated aq. brine (20 mL), combined, dried(sodium sulfate), decanted, and evaporated to give the title compound as27 mg of colorless oil.

[0615]¹H NMR (400 MHz, CD₃OD): δ 7.51-7.40 (m, 5H), 2.98 (dm, J=12 Hz,2H), 2.53 (td, J=12 and 3 Hz, 2H), 2.24-2.10 (m, 2H), 1.65 (bd,J=12 Hz,2H), 1.42-1.26 (m, 3H), 1.06 (qd, J=12 and 4 Hz, 2H).

[0616] HPLC/MS (ESI): m/z 240 (M+H); HPLC: 2.25 min.

Procedure 17

[0617] 4-(3,3-Difluoro-3-(4-fluorophenyl)prop-1-yl)piperidine

[0618] Step A: 1-(t-Butoxycarbonyl)-4-(hydroxymethyl)piperidine

[0619] Di-t-butyl dicarbonate (4.69 g, 21.5 mmol) was transferred inmethylene chloride (9 mL) over 10 min. to a solution of4-(hydroxymethyl)piperidine (2.47 g, 21.4 mmol) in methylene chloride(16 mL). After stirring at rt for I h, the solution was diluted withether (50 mL) and washed with 2 N aq. HCl, saturated aq. sodiumbicarbonate, and saturated aq. brine (25 mL of each). The organic layerwas dried (sodium sulfate), decanted, and evaporated to give 4.57 g ofthe title compound as a crystalline solid.

[0620]¹H NMR (500 MHz, CD₃OD): δ 4.08 (d, J=14 Hz, 2H), 3.40 (d, J=6 Hz,2H), 2.81-2.67 (m, 2H), 1.71 (d, J=13 Hz, 2H), 1.67-1.58 (m, 1H), 1.44(s, 9H), 1.09 (qd, J=12 and 4 Hz, 2H).

[0621] Step B: 1-(t-Butoxycarbonyl)-4-(iodomethyl)piperidine

[0622] Methanesulfonyl chloride (4.10 mL, 6.07 g, 52.9 mmol) was addeddropwise to a solution of1-(t-butoxycarbonyl)-4-(hydroxymethyl)piperidine from Step A (10.0 g,46.4 mmol) and triethylamine (9.80 mL, 7.11 g, 70.3 mmol) in methylenechloride (140 mL) at 5-8° C. After 1 h, the mixture was diluted withethyl acetate (400 mL) and washed with water (200 mL). The aqueous layerwas extracted with ethyl acetate (2×150 mL) and the combined organiclayers were washed with 1 N aq. HCl (200 mL), saturated aq. sodiumbicarbonate (200 mL), and saturated aq. brine (200 mL). The organiclayer was dried (sodium sulfate), decanted, and evaporated to give 13.58g of 1-(t-butoxycarbonyl)piperidin-4-yl methanesulfonate as a paleyellow solid.

[0623] A mixture of 1-(t-butoxycarbonyl)piperidin-4-yl methanesulfonate(13.58 g, 46.4 mmol) and sodium iodide (34.68 g, 232 mmol) in acetone(80 mL) was heated to reflux for 3 h. The mixture was partitionedbetween ether (350 mL) and water (350 mL). The organic layer was washedwith saturated aq. brine (250 mL), and the aqueous layers were extractedin succession with ether (250 mL). The combined organic layers weredried (sodium sulfate), decanted, and evaporated to give the titlecompound (14.8 g) as a pale yellow oil.

[0624]¹H NMR (500 MHz, CDCl₃): δ 4.25-4.00 (m, 2H), 3.12 (d, J=4 Hz,2H), 2.78-2.52 (m, 2H), 1.85 (d, J=13 Hz, 2H), 1.68-1.56 (m, 1H), 1.48(s, 9H), 1.15 (qd, J=12 and 4 Hz, 2H).

[0625] Step C:((1-(t-Butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide

[0626] A solution of triphenylphosphine (6.63 g, 25.3 mmol) and1-(t-butoxycarbonyl)-4-(iodomethyl)piperidine from Step B (7.96 g, 24.5mmol) in acetonitrile (40 mL) was heated to reflux for 72 h. Thesolution was evaporated to give 13.35 g of white solid. A portion (12.34g) of this material was dissolved in acetonitrile (25 mL) at 65° C.Ethyl acetate (35 mL) was added and the mixture was allowed to coolslowly to rt and then to −20° C. The supernatant was decanted, and thecolorless crystals were washed with ethyl acetate (5×5 mL) and driedunder vacuum to give 9.25 g of the title compound.

[0627]¹H NMR (500 MHz, CD₃OD): δ 7.89 (t, J=8 Hz, 3H), 7.86 (dd, J=12and 8 Hz, 6 H), 7.76 (td, J=8 and 4 Hz, 6H), 3.91 (bd, J=13 Hz, 2H),3.44 (dd, J=14 and 6 Hz, 2H), 2.72-2.58 (m, 2H), 2.08-1.96 (m, 1H), 1.49(bd, J=12 Hz, 2H), 1.41 (s, 9 H), 1.43 (qd, J=13 and 4 Hz, 2H).

[0628] Step D: Methyl (4-fluorobenzoyl)formate

[0629] Dimethyl oxalate (5.90 g, 50 mmol) was dissolved in THF (50 mL)and ether (50 mL) in a 3-neck round bottom flask fitted with amechanical stirrer. The solution was stirred vigorously at −65° C. as a1.0 M THF solution of 4-fluorophenylmagnesium bromide (60 mL, 60 mmol)was added dropwise over 40 min. The mixture was stirred 30 min at −65°C. and allowed to warm to −20° C. over 30 min before being poured into2N aq. HCl (50 mL) with stirring. The layers were separated and the aq.layer was extracted with ether (3×50 mL). The combined organic layerswere washed with saturated aq. brine (2×50 mL), dried (sodium sulfate),decanted, and evaporated. The residue was dissolved in ethyl acetate,dried (sodium sulfate), filtered, and evaporated to give a yellow solid.The crude product was dissolved in warm hexane (25 mL), filtered, andcooled to −20° C. Filtration followed by washing with cold hexane (15mL) gave 4.95 g of the title compound as light tan crystals.

[0630]¹H NMR (500 MHz, CDCl₃): δ 8.11 (dd, J=9 and 5, Hz, 2H), 7.21 (t,J=9 Hz, 2 H), 4.00 (s, 3H).

[0631] Step E: Methyl difluoro(4-fluorophenyl)acetate

[0632] Methyl (4-fluorobenzoyl)formate from Step D (4.75 g, 26.1 mmol)was added to (diethylamino)sulfur trifluoride (7.0 mL, 8.5 g, 53 mmol).The mixture was stirred rapidly and an ice bath was used briefly toreduce the temperature to 15° C. After the ice bath was removed, thereaction temperature rose to 48° C. over 10 min and then slowly returnedto rt. After a total of 2.75 h, the solution was carefully poured ontocrushed ice (30 g) and the mixture was extracted with methylene chloride(2×25 mL). The organic layers were washed in succession with saturatedaq. sodium bicarbonate (2×25 mL) and saturated aq. brine (10 mL),combined, dried (sodium sulfate) decanted, and evaporated. The residuewas distilled to give the title compound as 4.16 g of light yellowliquid, B.P. 46-48° C. (0.5 mm Hg).

[0633]¹H NMR (500 MHz, CDCl₃): δ 7.63 (dd, J=9, 5 Hz, 2H), 7.16 (d, J=9Hz, 2H), 3.88 (s, 3H).

[0634] Step F:1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-en-1-yl)piperidine

[0635] A solution of methyl difluoro(4-fluorophenyl)acetate (2.04 g,10.0 mmol) from Step E in methanol (10.0 mL) was cooled to −60° C.Sodium borohydride (380 mg, 10.0 mmol) was added in 5 portions at 10 to15 min. intervals. The mixture was cooled to −60 to −55° C. prior toeach addition and allowed to warm to −45° C. following each addition.After the last addition, the mixture was stirred 1.25 h at −50 to −45°C. The mixture was cooled to −60° C. and quenched with 1 N aq. HCl (30mL), with the temperature rising to −20° C. near the end of theaddition. After warming to 0° C., the mixture was extracted with ether(3×20 mL). The combined ether layers were washed with water (2×20 mL),dried (sodium sulfate), decanted, and evaporated to give 1.95 g of crude2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol as a pale yellow oil.

[0636] A suspension of((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide(500 mg, 0,92 mmol) from Step C in THF (7.2 mL) was stirred at rt for 30min. A 0.5 M toluene solution of potassium bis(trimethylsilyl)amide (1.8mL, 0.90 mmol) was added over 3 min., giving an orange suspension. After30 min., crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol (95 mg,0.46 mmol) was added in THF (1.0 mL). After an additional 30 min, themixture was quenched by the addition of saturated aq. NH₄Cl (2 mL). Themixture was partitioned between ethyl acetate (50 mL) and water (75 mL),and the aqueous layer was extracted with ethyl acetate (50 mL). Theorganic layers were washed in succession with saturated aq. brine (25mL), dried (sodium sulfate), decanted, and evaporated. The crude productwas purified by FC, eluting with 10% ether in hexane to give 117 mg ofthe title compound as a 95:5 mixture of cis and trans isomers,respectively.

[0637]¹H NMR (500 MHz, CDCl₃): δ 7.55 (dd, J=9 and 5 Hz, 2H), 7.13 (t,J=9 Hz, 2 H), 5.76 (q, J=12 Hz, 1H), 5.64 (dd, J=12 and 10 Hz, 1H),4.20-3.95 (m, 2H), 2.80-2.54 (m, 3H), 1.54 (bd, J=12 Hz, 2H), 1.47 (s,9H), 1.26 (qd, J=12 and 4 Hz, 2H).

[0638] Step G:1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperidine

[0639] Potassium azodicarboxylate (695 mg, 3.58 mmol) was added to asolution of 1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-en-1-yl)piperidine from Step F (424mg, 1.19 mmol) in methanol (3.3 mL). The mixture was stirred at rt as a9.0 M solution of acetic acid in methanol (0.80 mL, 7.2 mmol) was addedover 3 h using a syringe pump. After 30 min., a second portion ofpotassium azodicarboxylate (695 mg, 3.58 mmol) was added followed by theaddition of 9.0 M acetic acid in methanol (0.80 mL, 7.2 mmol) over 3 h.After 20 min, a third portion of potassium azodicarboxylate (695 mg,3.58 mmol) was added followed by the addition of 9.0 M acetic acid inmethanol (0.80 mL, 7.2 mmol) over 3 h. After stirring for 20 h at rt,the mixture was diluted with ethyl acetate (80 mL), and washed with 2 Naq. HCl (40 mL), saturated aq. sodium bicarbonate (40 mL), and saturatedaq. brine (40 mL). The organic layer was dried (sodium sulfate),decanted, and evaporated to give 417 mg of a mixture containing thetitle compound and 20-25% of unreduced1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-en-1-yl)piperidine.

[0640] A portion (365 mg) of the crude mixture containing residualolefin was hydrogenated at atmospheric pressure for 16 h using iridiumblack (30 mg) in a mixture of t-butanol (24 mL) and ethyl acetate (2.4mL). The mixture was filtered, the catalyst was washed with methanol,and the filtrate was evaporated to give 371 mg of the title compound asa pale yellow syrup. R_(f): 0.2 (5% ethyl acetate in hexane).

[0641]¹H NMR (500 MHz, CDCl₃): δ 7.46 (dd, J=9 and 5 Hz, 2H), 7.12 (t,J=9 Hz, 2 H), 4.18-4.00 (m, 2H), 2.73-2.61 (m, 2H), 2.14 (tm, J=16 Hz,2H), 1.64 (bd, J=12 Hz, 2H), 1.46 (s, 9H), 1.46-1.33 (m, 3H), 1.08 (qd,J=12 and 4 Hz, 2H).

[0642] Step H: 4-(3,3-Difluoro-3-(4-fluorophenyl)prop-1-yl)piperidine

[0643]1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-yl)piperidinefrom Step G (122 mg, 0.34 mmol) was dried by evaporation of a toluenesolution at reduced pressure. The residue was dissolved in chloroform(7.6 mL) and iodotrimethylsilane (0.100 mL, 141 mg, 0.70 mmol) wasadded. After stirring 30 min at rt, the solution was poured into amixture of saturated aqueous sodium bicarbonate (15 mL) and 2.5 N aq.NaOH (5 mL), and extracted with ether (50 mL). The organic layer waswashed with saturated aq. brine (15 mL), dried (sodium sulfate),decanted, and evaporated to give the title compound as 88 mg ofcolorless oil.

[0644]¹H NMR (500 MHz, CD₃OD): δ 7.51 (dd, J=9 and 5 Hz, 2H), 7.17 (t,J=9 Hz, 2 H), 2.98 (dm, J=12 Hz, 2H), 2.52 (td, J=12, 3 Hz, 2H), 2.17(tm, J=16 Hz, 2H), 1.65 (bd, J=13 Hz, 2H), 1.42-1.26 (m, 3H), 1.07 (qd,J=12 and 4 Hz, 2H).

[0645] HPLC/MS (ESI): mlz 258 (M+H); HPLC: 2.64 min.

Procedure 18

[0646] 4-(2-((4-Fluorophenyl)sulfonyl)eth-1-yl)piperidineTrifluoroacetic Acid Salt

[0647] Step A: 4-(2-Hydroxyeth-1-yl)piperidine Acetic Acid Salt

[0648] Combined 4-(2-hydroxyeth-1-yl)pyridine (25 g, 0.2 mol) andplatinum oxide (1 g, 4.4 mmol) in 400 mL acetic acid. Placed under 45psi hydrogen at 60° C. for 24 h. Decanted, then filtered through Celiteand removed the solvent to afford 38 g (100%) of the crude product,which was used without further purification.

[0649] Step B: 4-(2-Hydroxyeth-1-yl)-1-tert-butoxycarbonylpiperidine

[0650] Dissolved sodium bicarbonate (134 g, 1.6 mol) and4-(2-hydroxyeth-1-yl)piperidine acetic acid salt (38 g, 0.2 mol, fromStep A) in 500 mL of 50% tetrahydrofuran in water. Added di-tert-butyldicarbonate (35 g, 0.2 mol) and stirred at rt overnight. Diluted withethyl acetate and extracted the aq. layer with 2×300 mL of ethylacetate. Washed the combined organic layers with 2×300 mL of 1 N HCl andbrine. Dried over magnesium sulfate and concentrated to afford 37.4 g(81%) of the title compound.

[0651] ESI-MS: 230 (M+H); HPLC A: 2.76 min.

[0652] Step C: 4-(2-Iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine

[0653] Combined 4-(2-hydroxyeth-1-yl)-1-tert-butoxylcarbonylpiperidine(37.4 g, 0.16 mol, from Step B), triphenylphosphine (55 g, 0.21 mol) andimidazole (14 g, 0.21 mol) in 800 mL of 33% acetonitrile in ether.Cooled to 0° C. and added iodine (56 g, 0.22 mol) portionwise. Theiodine is de-colored until the endpoint of the reaction. Diluted with 1L of ether. Washed organic layer with 2×500 mL each of sat'd. aq.Na₂S₂O₃, sat. aq. CuSO₄ and brine. Dried over magnesium sulfate,filtered and concentrated. Triphenylphosphine oxide precipitates. Addedether and filtered the slurry through a plug of silica gel. Purified aportion of the crude material by flash chromatography (5% ethyl acetatein hexane eluent) to afford the title compound.

[0654]¹H-NMR (400 MHz, CDCl₃): δ 4.10 (br s, 2H), 3.23 (t, 2 H, J=7.2Hz), 2.72 (br t, 2 H, 12.3 Hz), 1.79 (q, 2 H, J=7 Hz), 1.67 (br d, 2H,14 Hz), 1.61 (m, 1H), 1.47 (s, 9H), 1.14 (qd, 2 H, J=4.3, 12 Hz);ESI-MS: 340 (M+H); HPLC A: 3.74 min.

[0655] Step D:4-(2-(4-Fluorophenylthio)eth-1-yl)-1-tert-butoxycarbonylpiperidine

[0656] To a slurry of sodium hydride (47 mg, 60% in mineral oil, 1.2mmol) in tetrahydrofuran at 0° C. was added 4-fluorothiophenol (0.1 mL,0.94 mmol). The reaction mixture was warmed to rt. for 20 min, followedby addition of 4-(2-iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine (265mg, 0.78 mmol, from Step C). The reaction was then heated to reflux for10 min, cooled and diluted with ether. The organic layer was washed with1 N NaOH, dried over magnesium sulfate and concentrated to provide 252mg (95%) of the title compound. ESI-MS: 340.0 (M+H); HPLC A: 4.07 min.

[0657] Step E: 4-(2-(4-Fluorophenylsulfonyl)eth-1-yl)piperidinetrifluoroacetic Acid Salt

[0658] Added a solution of oxone (1.14 g, 1.86 mmol) in water to asolution of4-(2-(4-fluorophenylthio)eth-1-yl)-1-tert-butoxycarbonylpiperidine (252mg, 0.74 mmol, from Step D) in methanol at 0° C. Warmed to rt. After 90min., added an additional 0.5 g of oxone. After 3 h, the reactionmixture was diluted with methylene chloride and washed with 1 N NaOHcontaining sodium bisulfite. The aq. layer was extracted twice withmethylene chloride, and the combined organic layers were dried overmagnesium sulfate. The solution was concentrated and dissolved in 5%trifluoroacetic acid in methylene chloride for I h. The solvent wasevaporated to afford 297 mg (100%) of the title compound.

[0659] ESI-MS: 239.8 (M+H); HPLC A: 2.54 min.

Procedure 19

[0660] 4-((5-Benzyl)pyrid-3-yl)piperidine di-TFA Salt

[0661] Step A:N-tert-Butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-trifluoromethaneSulfonate.

[0662] A dry flask under nitrogen was charged with a solution of sodiumhexamethyldisilazide (11 mL, 1.0 M in THF) and was cooled to −78° C. Asolution of N-tert-butoxycarbonyl4-piperidone (2.0 g, 10 mmol) in 10 mLTHF was added dropwise via cannula. After 30 min. a solution of2-(N,N-bis(trifluoromethanesulfonyl)amino-5-chloropyridine (4.7 g, 12mmol) in 15 mL THF was added. The mixture was warmed to roomtemperature, quenched with sat'd ammonium chloride and extracted withethyl acetate. The ethyl acetate layer was separated and washed withsat'd brine then dried over sodium sulfate and concentrated. Flashchromatography (100 g silica, 10/1 Hexane/ethyl acetate) afforded 1.9 g(58%) of the title compound.

[0663]¹H NMR (400 MHz, CDCl₃). δ 1.5 (s, 9H), 2.4-2.48 (m, 2H),3.62-3.68 (t, 2H), 4.05-4.07 (m, 2H), 5.77-5.8 (bs, 1H).

[0664] Step B:N-tert-Butoxycarbonyl-4-trimethylstannyl-1,2,5,6-tetrahydropyridine

[0665] A dry flask under nitrogen was charged with 20 mL THF, lithiumchloride (1.6 g, 37.3 mmol), tetrakistriphenylphosphine palladium(0),(331 mg, 0.28 mmol) and hexamethyldistannane (1.2 mL, 5.7 mmol).N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-trifluoromethanesulfonate (1.9 g, 5.7 mmol) was added and the mixture was stirredovernight at 60° C. The mixture was diluted with water and extractedwith ethyl acetate (3×150 mL). The combined organic layers were driedover sodium sulfate and concentrated. Flash chromatography (100 gsilica, 20/1 Hexane/ethyl acetate) afforded 1.56 g (79%) of the titlecompound.

[0666]¹H NMR (300 MHz, CDCl₃). δ 0.5 (s, 9H), 1.5 (s, 9H), 2.25-2.35 (m,2H), 3.62-3.68 (t, 2H), 3.95-3.97 (m, 2H), 5.77-5.8 (bs, 1H).

[0667] Step C: 3-Bromo-5-benzylpyridine

[0668] A dry flask under nitrogen was charged with zinc chloride (16 mL,0.5 M in THF, 8 mmol), and a solution of phenylmagnesium chloride (4 mL,2.0 M in THF, 8 mmol). The mixture was heated to 50° C. for 3h thencooled to room temperature and transferred via cannula to a solution of3,5-dibromopyridine (1.26 g, 5.3 mmol), copper iodide (61 mg, 0.32mmol), and bis(diphenylphosphino)ferrocene palladium dichloride (218 mg,0.27 mmol) in 15 mL THF. The resulting mixture was heated to 50° C.overnight. Sat'd ammonium chloride was added and the mixture wasextracted with ethyl acetate. The organic portion was dried over sodiumsulfate and concentrated. Flash chromatography (8/1 hexanelethylacetate) afforded 433 mg (33 %) of the title compound. ¹H NMR (400 MHz,CDCl₃). δ 4.02 (s, 2H), 7.18-7.4 (m, 8H), 7.65 (s, 1H).

[0669] Step D: 4-((5-Benzyl)pyrid-3-yl)piperidine di-TFA

[0670] A flask was purged with nitrogen and charged with DMF,3-bromo-5-benzylpyridine (618 mg, 2.5 mmol, from Step C), tetrakistriphenylphosphine palladium (58 mg, 0.05 mmol), andN-tert-butoxycarbonyl-4-trimethylstannyl-1,2,5,6-tetrahydropyridine(1.04 g, 3 mmol). The mixture was heated to 100° C. and stirred for 10h. An additional portion of tetrakis triphenylphosphine palladium (40mg, 0.03 mmol) was added and stirring was continued for 14 h. Thesolution was cooled and diluted with ethyl acetate then washed withwater, dried over sodium sulfate and concentrated. Flash chromatography(2.5/1 hexane/ethyl acetate) afforded 590 mg (67%) of the couplingproduct. The product was dissolved in 4 mL methanol and 50 mg 10% Pd/Cwas added. The mixture was stirred under 1 atm of hydrogen for 3 h. Thecatalyst was filtered off and the residue was dissolved in 1/1TFA/methylene chloride. Removal of the solvent and drying under vacuumafforded the title compound as its TFA salt.

[0671]¹H NMR (500 MHz, CDCl₃). δ 1.55-1.64 (m, 2H), 1.75-1.8 (d, 2H),2.57-2.62 (m, 1H), 2.68-2.73 (t, 2H), 3.15-3.2 (d, 2H), 7.14-7.15 (d,2H), 7.19-7.21 (m, 1H), 7.26-7.32 (m, 3H), 8.30-8.31 (d, 2H).

Procedure 20

[0672] 4-(2-(Benzyl)-(2H)-tetrazol-5-yl)piperidine

[0673] Step A: 1-(t-Butoxycarbonyl)-4-cyanopiperidine

[0674] Isonipecotamide (10.0 g, 78.0 mmol) was added in portions to 25mL of POCl₃ at 0° C. The cooling was removed and the mixture was allowedto reach rt. The mixture was heated at reflux for 2 h, then cooled tort. The mixture was poured onto 100 g of ice. The pH of the aqueousmixture was adjusted to 11 with solid KOH and extracted with 4×200 mL ofmethylene chloride. The extracts were combined, dried over magnesiumsulfate and concentrated to afford 8.0 g of crude (4-cyano)piperidine.

[0675] The crude (4-cyano)piperidine was dissolved in 50 mL of methanoland treated with 17.0 g (78.0 mmol) of di-t-butyl dicarbonate and theresulting mixture was stirred at rt for 1 h. The mixture wasconcentrated. Flash chromatography on 250 g of silica gel using 1:1 v/vhexanes/ether afforded 13.4 g (80%) of the title compound:

[0676]¹H NMR (300 MHz) δ 1.46 (s, 9H), 1.76-1.96 (4H), 2.78-2.82 (m,1H), 3.31-3.37 (m, 2H), 3.63-3.69 (m, 2H).

[0677] Step B: 1-(t-Butoxycarbonyl)4-(1H-tetrazol-5-yl)piperidine

[0678] A mixture of 2.10 g (10.0 mmol) of1-(t-butoxycarbonyl)-4-cyanopiperidine (from Step A), 1.95 g (30.0 mmol)of sodium azide and 1.60 g (30.0 mmol) of ammonium chloride in 20 mL ofDMF was stirred at 100° C. for 20 h. The mixture was cooled andpartitioned between 200 mL of methylene chloride and 200 mL of 1.0 N HCland the layers were separated. The organic layer was washed with 200 mLof water, dried over magnesium sulfate and concentrated. Flashchromatography on 50 g of silica gel using 4:1 v/v methylenechloride/ethyl acetate+1% acetic acid, then 2:1 v/v methylenechloride/ethyl acetate+1% acetic acid as the eluent afforded 1.51 g(60%) of the title compound:

[0679]¹H NMR (500 MHz) δ 1.49 (s, 9H), 1.83-1.89 (m, 2H), 2.13-2.15 (m,2H), 2.96-3.04 (m, 2H), 3.13-3.36 (m, 1H), 4.14-4.22 (m, 2H).

[0680] Step C:1-(t-Butoxycarbonyl)-4-((1-benzyl)-(1H)-tetrazol-5-yl)piperidine and1-(t-Butoxycarbonyl)-4-((2-benzyl)-(2H)-tetrazol-5-yl)piperidine

[0681] A solution of 438 mg (1.7 mmol) of1-(t-butoxycarbonyl)4-(1H-tetrazol-5-yl)piperidine (from Step B) in 2 mLof DMF at 0° C. was treated with 83 mg (0.50 mmol) of sodium hydride(60% in mineral oil) and 0.41 mL (3.4 mmol) of benzyl bromide. Theresulting mixture was warmed to rt and stirred for 2.5 h. The mixturewas partitioned between 50 mL of ether and 50 mL of water and the layerswere separated. The organic layer was washed with 50 mL sat'd brine,dried over magnesium sulfate and concentrated. Flash chromatographyusing 2:1 v/v methylene chloride/ether, then 1:2 v/v methylenechloride/ether afforded 85 mg (15%) of1-(t-butoxycarbonyl)-4-(2-(benzyl)-(2H)tetrazol-5-yl)piperidine. Elutionwith 2:1 v/v ethyl acetate/methylene chloride afforded 95 mg (17%) of1-(t-butoxycarbonyl)-4-(1-(benzyl)-(1H)-tetrazol-5-yl)piperidine.

[0682] For1-(t-butoxycarbonyl)4-(2-(benzyl)-(2H)-tetrazol-5-yl)piperidine: ¹H NMR(500 MHz) δ 1.47 (s, 9H), 1.76-1.84 (2H), 2.02-2.05 (2H), 2.91-2.95(2H), 3.07-3.12 (m, 1H), 4.00-4.20 (2H), 5.71 (s, 2H), 7.35-7.40 (5H).

[0683] For1-(t-butoxycarbonyl)-4-(1-(benzyl)-(1H)-tetrazol-5-yl)piperidine: ¹H NMR(500 MHz) δ 1.45 (s, 9H), 1.59-1.61 (2H), 1.76-1.84 (2H), 2.70-2.80(2H), 2.85-2.89 (m, 1H), 4.004.20 (2H), 5.55 (s, 2H), 7.17-7.19 (2H),7.36-7.39 (3H).

[0684] Step D: 4-(2-(Benzyl)-(2H)-tetrazol-5-yl)piperidine

[0685] A solution of 85 mg (0.25 mmol) of1-(t-butoxycarbonyl)4-((2-benzyl)tetrazol-5-yl)piperidine (from Step C)in 2 mL of 1:1 v/v methylene chloride/TFA was stirred at rt for 2 h. Thesolution was concentrated. Flash chromatography on silica gel using19:1:0.1 v/v/v methylene chloride/methanol/NH₄0H as the Eluant afforded57 mg (94%) of the title compound.

Procedure 21

[0686]4-(1-(4-Methylsulfonylbenzyl)-3-ethyl-(1H)-pyrazol-4-yl)piperidineDi-TFA Salt

[0687] Step A: N-tert-Butoxycarbonyl-4-piperid-4-ylacetaldehyde

[0688] A solution of oxalyl chloride (2.4 mL, 27.5 mmol) in 125 mLmethylene chloride was cooled to −78° C. and DMSO (3.3 mL, 47.1 mmol)was added slowly. After 10 min a solution of2-(N-tert-butoxycarbonylpiperidin-4-yl)ethanol (4.5 g, 19.6 mmol) in 10mL methylene chloride was added. The mixture was stirred for 20 min thentriethylamine (13.6 mL, 98.1 mmol) was added and the mixture was warmedto room temperature. After 30 min the mixture was diluted with ethylacetate and washed with water (3×). The organic portion was dried oversodium sulfate and concentrated. Flash chromatography (3/1 hexane/ethylacetate) afforded 3.7 g (83%) of the desired aldehyde.

[0689]¹H NMR (400 MHz, CDCl₃). δ 1.13-1.43 (m, 2H), 1.48 (s, 9H),1.68-1.77 (m, 2H), 2.04-2.11 (m, IH), 2.38-2.41 (d, 2H), 2.71-2.8 (m,2H), 4.04-4.14 (m, 2H), 9.8 (s, 1H).

[0690] Step B:3-Ethyl-4-(N-t-butoxycarbonylpiperidin-4-yl)-(1H)-pyrazole

[0691] A solution of N-tert-butoxycarbonylpiperidin-4-ylacetaldehyde(4.5 g, 19.8 mmol, from Step A), and morpholine (1.7 mL, 19.8 mmol) in100 mL benzene was refluxed using a dean-stark apparatus. Afterrefluxing over night the mixture was concentrated to provide theenamine. The crude enamine was dissolved in 40 mL methylene chloride andthe solution was cooled to 10° C. Propionyl chloride (1.7 mL, 19.8 mmol)and then triethylamine (1.4 mL, 9.9 mmol) were added. The mixture wasgradually warmed to room temperature and stirred for 40 h thenconcentrated. The residue was dissolved in 60 mL of ethanol andhydrazine (6.2 mL, 198 mmol) was added. The solution was refluxed for 5h. The solvent was removed and ethyl acetate was added. The organic waswashed with water and sat'd sodium chloride then dried over magnesiumsulfate and concentrated. Flash chromatography (0.5% methanol/methylenechloride→2% methanol/methylene chloride) afforded 2.1 g (38 %) of thetitle compound.

[0692]¹H NMR (400 MHz, CDCl₃). δ 1.25-1.31 (t, 3H), 1.44-1.57 (m, 1H),1.46 (s, 9H), 1.78-1.83 (s, 2H), 2.53-2.6 (m, 1H), 2.62-2.7 (q, 2H),2.77-2.82 (m, 2H), 4.12-4.23 (m, 2H), 7.32 (s, 1H).

[0693] Step C:4-(1-(4-Methylsulfonylbenzyl)-3-ethyl-(1H)-pyrazol-4-yl)-N-t-butoxylcarbonylpiperidine

[0694] A dry flask was charged with 5 mL DMF and sodium hydride (224 mg,60% dispersion in mineral oil, 5.6 mmol). A solution of3-ethyl-4-(N-t-butoxycarbonylpiperidin-4-yl)-(1H)-pyrazole (1.3 g, 4.7mmol, from Step B) in 5 mL DMF was added. The mixture was stirred for 1h at room temperature and a solution of (4-methylsulfonyl)benzylchloride (1.05 g, 5.2 mmol) in 5 mL DMF was added. After 3 h the solventwas removed and the product was purified by preparative HLC (35%acetonitrile/water ->85% acetonitrile/water, C-18 stationary phase) togive 0.5 g of product as a mixture of isomeric N-alkylation products.The isomers were separated by preparative HPLC using a chiral stationaryphase (Chiracel-OJ, 1/1 hexane/ethanol) to provide 210 mg (10%) of thedesired isomer along with 70 mg (3%) of the undesired isomer. Thesubstitution pattern of both isomers was determined by NOE difference.

[0695]¹H NMR (400 MHz, CDCl₃, desired isomer). δ 1.25-1.31 (t, 3H),1.38-1.47 (m, 1H), 1.46 (s, 9H), 1.8-1.85 (m, 2H), 2.5-2.6 (m, 1H),2.6-2.66 (q, 2H), 2.75-2.82 (m, 2H), 3.03 (s, 3H), 4.13-4.22 (m, 2H),5.32 (s, 2H), 7.13 (s, 1H), 7.28-7.31 (d, 2H), 7.89-7.91 (d, 2H).

[0696] Step D:4-(1-(4-Methylsulfonylbenzyl)-3-ethyl-(1H)-pyrazol-4-yl)piperidinedi-TFA Salt

[0697]4-((1-(4-Methylsulfonylbenzyl)-3-ethyl)-(1H)-pyrazol-4-yl)-N-t-butoxylcarbonylpiperidinefrom Step C was treated with TFA for 1 h and evaporated to afford thetitle compound as the TFA salt.

Procedure 22

[0698] 4-(2-Benzylthiazol-5-yl)piperidine di-HCl Salt (Method A)

[0699] Step A: 1-t-Butyloxycarbonyl-4-(nitromethylcarbonyl)piperidine

[0700] To a solution of 1-t-butyloxycarbonylpiperidine-4-carboxylic acid(22.9 g, 100 mmol) in 200 mL of anhydrous THF was added carbonyldiimidazole (20.0 g, 125 mmol) under nitrogen. Effervescence wasobserved and the reaction mixture was stirred 1 h at ambienttemperature. Freshly distilled nitromethane (7.4 mL, 135 mmol) followedby DBU (21.0 mL, 140 mmol) were added. The resulting reaction mixturewas stirred for 1 day at room temperature. After dilution with ethylacetate, the mixture was washed with 2N HCl and brine. The organic phasewas dried over anhydrous magnesium sulfate. Evaporation of the solventfollowed by the purification of the residue on silica gel using 1:1mixture of ethyl acetate -hexane with 1% acetic acid as an eluent gave25 g of the nitroketone as a semi solid. After removal of last traces ofacetic acid by azeotroping with toluene.

[0701]¹H NMR (CDCl₃) 1.48 (9H, s); 1.65, 1.90, 2.65, 2.80, 4.15 (allmultiplets); 5.36 (2H, s).

[0702] Step B:1-t-Butyloxycarbonyl-4-(1-hydroxy-2-nitro)ethyl)piperidine

[0703] Sodium borohydride (1.52 g, 40 mmol) was added portionwise to asuspension of 1-t-butyloxycarbonyl-4-(nitromethylcarbonyl) piperidine(10.5 g, 40 mmol) from Step A in methanol (80 mL) at 0° C. After 6.5 h,the solvent was removed in vacuo. The residue was diluted with ethylacetate and stirred with 2N HCI and the layers were separated. Theorganic phase was washed with brine and dried over magnesium sulfate.Solvent removal gave 9.1 g of the desired product as amorphous solid.

[0704]¹H NMR(CDCl₃) 1.45 (9H, s); 4.45 (2H, m); 1.3, 1.65, 1.85, 2.7,4.2 (multiplets)

[0705] Step C: 1-t-Butyloxycarbonyl-4-(1-hydroxy-2-amino)ethylpiperidine

[0706] To a stirred suspension of1-t-butyloxycarbonyl-4-(1-hydroxy-2-nitro)ethyl)piperidine (9.0 g, 33mmol) from Step B in anhydrous methanol (100 mL), 10% Pd—C (2.0 g)followed by ammonium formate (12.6 g, 200 mmol) were cautiously added.The reaction mixture was stirred 1.5 days at ambient temperature. Thecatalyst was filtered through a pad of celite and washed with methanol.The filtrate was concentrated after adding 42 mL of triethylamine tofree the product from any formic acid salts. The residue was purified onsilica gel using 10:10:1 mixture of ethyl acetate, hexane and NH₄OH assolvent to yield 6.9 g of the desired amino alcohol as white solid afterazeotroping with toluene.

[0707]¹H NMR (CDCl₃): 1.5 (9H, s); 3.6 (2H, s) 1.2, 1.75, 2.6, 3.24,3.4, 4.15 (all multiplets).

[0708] Step D:1-t-Butyloxycarbonyl-4-(1-hydroxy-2-phenylacetylamino)ethylpiperidine

[0709] Phenylacetyl chloride (0.44 mL, 3.3 mmol) was added dropwise to amixture of 1-t-butyloxycarbonyl-4-(1-hydroxy-2-amino)ethylpiperidine(0.732 g, 3 mmol) from Step C and triethylamine (0,465 mL, 3.3 mmol) inmethylene chloride (15 mL) at ice bath temperature and the bath wasremoved. After stirring for 3 h at room temperature, the reactionmixture was diluted with ethyl acetate and washed with saturated sodiumbicarbonate and brine. The organic phase was dried over anhydrousmagnesium sulfate. Solvent removal gave a crude product which was usedin the next step without further purification.

[0710]¹H NMR (CDCl₃) 1.45 (9H, s); 3.42 (2H, s); 1.2, 1.75, 2.6, 3.2,3.42, 4.12 (all multiplets).

[0711] Step E:1-t-Butyloxycarbonyl-4-(2-phenylacetamido)acetylpiperidine

[0712] To a stirred solution of1-t-butyloxycarbonyl-4-(1-hydroxy-2-phenylacetylamino)ethylpiperidinefrom Step D in acetone at ice bath temperature 8 N Jones reagent wasadded until the orange color of the reagent persisted. After stirringfor 0.5 h, 0.2 mL of isopropanol was added and the stirring wascontinued for 0.5 h. Solvent was removed in vacuo and the residue waspartitioned between water and ethyl acetate. The organic phase waswashed with brine and dried over anhydrous magnesium sulfate. Solventremoval gave an oil which was purified on silica gel using 1: ethylacetate—hexane as solvent to yield 606 mg of the desired ketone as oil.

[0713]¹H NMR (CDCl₃): 1.46 (9H, s); 3.62 (2H, s); 4.18 (2H, d, J=2);1.45, 1.8, 2.5, 2.78, 4.1, 7.35, 7.4 (all multiplets)

[0714] Step F: 1-t-Butyloxycarbonyl-4-(2-benzylthiazol-5-yl)piperidine

[0715] A mixture of1-t-butyloxycarbonyl-4-(2-phenylacetamido)acetylpiperidine (595 mg,1.653 mmol) from Step E and Lawesson's reagent (607 mg, 1.66 mmol) in 5mL of toluene was heated to 120° C. for 3.5 h. After cooling, 3:1mixture of ethyl acetate and methylene chloride and saturated sodiumbicarbonate solution were added and the mixture was stirred for 0.5 h.The organic phase was separated and washed with brine. Solvent removalgave a crude product which was purified on silica gel using 2:3 mixtureof ethyl acetate -hexane as solvent to give 330 mg of the desiredproduct.

[0716]¹H NMR (CDCl₃): 1.45 (9H, s); 4.4 (2H, s); 7.46 (1H, s); 1.58,1.95, 2.85, 2.95, 4.2 (all multiplets).

[0717] Step G: 4-(2-Benzylthiazol-5-yl)piperidine Di-Hydrochloride

[0718] Acetyl chloride (0.3 mL) was added dropwise to a solution1-t-butyloxycarbonyl-4-(2-benzylthiazol-5-yl)piperidine from Step F inmethanol (2 mL) at ice bath temperature. The reaction mixture wasstirred 3.5 h as it warmed to room temperature. Solvent removal in vacuogave the desire amine as glassy solid.

[0719]¹H NMR (CD₃OD): 4.58 (2H, s); 8.02 (1H, s); 1.94, 2.24, 3.15,3.35, 3.45 (all multiplets)

Procedure 23

[0720] 4-(2-Benzylthiazol-5-yl)piperidine Di-HCl Salt (Method B)

[0721] Step A: 1-t-Butyloxycarbonyl-4-(2-hydroxyethyl)piperidine

[0722] A mixture of 4-(2-hydroxyethyl) piperidine (5.0 g, 40 mmol),di-t-butyl dicarbonate (10.9 g, 50 mmol), and triethylamine (7 mL, 50mmol) in 100 mL of anhydrous methylene chloride was stirred overnight atroom temperature. Volatiles were removed in vacuo and the resulting oilwas purified on a silica gel column using 20% ethyl acetate in hexane aseluent to give 7.9 g of the desired product as a colorless oil.

[0723] Step B: 1-t-Butyloxycarbonyl-4-formylylmethylpiperidine

[0724] Oxalyl chloride (2.2 mL, 25 mmol) was added to 75 mL of anhydrousmethylene chloride at −78° C. DMSO (3.5 mL, 50 mmol) was then addeddropwise over 5 min, and the resulting mixture was stirred for 15 min.1-t-Butyloxycarbonyl-4-(2-hydroxyethyl)piperidine (2.29 g, 10 mmol, StepA) was dissolved in 5 mL of anhydrous methylene chloride and added over10 min to the above mixture. After stirring 30 min, DIEA (17.4 mL, 100mmol) was added over 10 min. The mixture was then warmed to 0° C. andmaintained at that temperature for 1 h. After quenching with water, thereaction mixture was diluted with 75 mL of methylene chloride and thelayers were separated. The organic phase was washed with 3×50 mL ofwater and dried over anhydrous magnesium sulfate. Solvent removal gavean oil, which was purified on silica gel using 20% ethyl acetate inhexane to give 2.05 g of the desired aldehyde which hardened overnightinto an oily solid.

[0725] NMR: δ 2.15 (2H, d, J=3); 9.8 (1H, s); 1.2, 1.5, 1.7, 2.75, 4.1(all multiplets)

[0726] Step C: 1-t-Butyloxycarbonyl4-(α-bromo-formylmethyl)piperidine

[0727] A mixture of 1-t-butyloxycarbonyl-4-formylylmethylpiperidine(0.57 g, 2.25 mmol, step B), 3,3-dibromo-Meldrum's acid (0.75 g, 2.5mmol) in 10 mL of anhydrous ether was stirred for 2 days at roomtemperature under nitrogen. The reaction mixture was diluted with ethylacetate and washed with sat'd. sodium bicarbonate solution. The organicphase was dried over anhydrous magnesium sulfate. Solvent removal andpurification on silica gel using 20% ethyl acetate in hexane as solventgave 59% of the pure bromo aldehyde as a colorless oil.

[0728]¹H NMR: δ (CDCl₃): 4.04 (1H, dd; J=1.5; 2); 9.46 (1H, d; J=1.5)1.35, 1.7, 1.95, 2.1, 2.75, 4.2 (all multiplets)

[0729] Step D: 1-t-Butyloxycarbonyl-4-(2-benzylthiazol-5-yl)piperidine

[0730] A mixture of1-t-butyloxycarbonyl-4-(α-bromo-formylmethyl)piperidine (612 mg, 2mmol), benzyl thioamide (500 mg, 2.55 mmol) in 10 mL of anhydroustoluene was heated to reflux for 6 h. Solvent was then removed and theresidue was purified on silica gel using 25% ethyl acetate in hexane assolvent to give 350 mg of the desired thiazole as an oil.

[0731]¹H NMR (CDCl₃): 1.45 (9H, s); 4.4 (2H, s); 7.46 (1H, s); 1.58,1.95, 2.85, 2.95, 4.2 (all multiplets).

[0732] Step E: 4-(2-Benzylthiazol-5-yl)piperidine Di-Hydrochloride

[0733] The title compound was prepared by removal of the protectinggroup of 1-t-butyloxycarbonyl-4-(2-benzylthiazol-5-yl)piperidine asdescribed in

EXAMPLE 22, Step G. Procedure 24

[0734] 4-(2-Benzyl-4-methylthiazol-5-yl)piperidine

[0735] The title thiazole was prepared according to the method ofProcedure 22 by substituting nitroethane for nitromethane in Step A.

Procedure 25

[0736] 4-(2-Benzyl-4-ethylthiazol-5-yl)piperidine

[0737] The title compound was obtained by the procedure of Procedure 22by substituting nitropropane for nitromethane in Step A.

Procedure 26

[0738] 4-(2-(2-Pyridylmethyl)thiazol-5-yl)piperidine Di-HCl Salt

[0739] Step A:1-t-Butyloxycarbonyl-4-((1-hydroxy)-2-(2-pyridylmethyl)carbonylamino)ethylpiperidine

[0740] To 0.361 g (2.08 mmol) of 2-pyridyleacetic acid hydrochloride in8 mL of methylene chloride, 0.337 g (2.5 mmol) of1-hydroxybenzotriazole, 0.478 g (2.5 mmol) of EDC and 0.57 mL (5.2 mmol)of N-methylmorpholine were added. After 10 min 0.508 g (2.08 mmol) of1-t-butyloxycarbonyl-4-(2-amino-1-hydroxy)ethylpiperidine from Procedure22, Step C was added and the solution was stirred overnight. Thereaction was quenched with saturated sodium bicarbonate and extractedwith methylene chloride. The combined methylene chloride layer waswashed with brine, dried and concentrated. The residue waschromatographed on a flash column using a gradient of 5-10% methanol inethyl acetate containing 1% triethylamine to isolate 0.68 g of thedesired product.

[0741]¹H NMR (CDCl₃): δ 1.24 (m, 3H), 1.45 (s, 9H), 1.58 (m, 1H), 1.82(m, 1H), 2.6 (br, 2H), 3.21 (m, IH), 3.49 (m, 2H), 3.75 (s, 2H), 4.12(br, 2H), 7.22 (m, 1H), 7.29 (d, 1H), 7.69 (m, IH), 852 (m, 1H).

[0742] Step B:1-t-Butyloxycarbonyl-4-(2-(2-pyridylmethyl)carbonylamino)acetylpiperidine

[0743] To a solution of 0.22 nL (3.2 mmol) of DMSO in 1 mL of methylenechloride cooled in a dry ice-acetone bath, 0.14 mL (1.6 mmol) of oxalylchloride was added. After 0.5 h, 0.145 g of1-t-butyloxycarbonyl-4-((1-hydroxy)-2-(2-pyridylmethyl)carbonylamino)ethylpiperidine(Step A) in 1 mL of methylene chloride was added. After 1 h, 0.89 mL(6.38 mmol) of triethylamine was added, the cold bath was removed andthe reaction was stirred for 1.5 h. The solution was partitioned betweenwater and methylene chloride. The organic layer was washed with brine,dried and concentrated. The residue was purified on a prep TLC plateusing 5% methanol—ethyl acetate as an eluent to furnish 67 mg of thedesired product.

[0744]¹H NMR (CDCl₃): δ 1.45 (s, 9H),1.5-2.0 (m, 4H), 2.53 9m, 1H), 2.77(br, 2H), 3.79 (s, 2H), 4.1 (br, 2H), 4.22 (d, 2H), 7.2-8.0 (m, 3H),8.61 (d, 1H).

[0745] Step C:1-t-Butyloxycarbonyl-4-(2-(2-pyridylmethyl)thiazol-5-yl)piperidine

[0746] The title compound was prepared by reacting1-t-butyloxycarbonyl-4-(2-(2-pyridylmethyl)carbonylamino)acetylpiperidine(Step B) with Lawesson's reagent as described in Procedure 22, Step F.

[0747]¹H NMR (CDCl₃): δ 1.47 (s, 9H), 1.6 (m, 2H), 1.99 (m, 2H), 2.82(br, 2H), 2.94 (m, 1H), 4.17 (br, 2H), 4.48 (s, 2H), 7.2-7.8 (m, 4H),8.6 (br, 1H).

[0748] Step D: 4-(2-(2-Pyridylmethyl)thiazole-5-yl)piperidine Di-HClSalt

[0749] Removal of the t-butyloxycarbonyl protecting group as describedin Procedure 22, Step G furnished the title compound.

Procedure 27

[0750] 4-(Imidazo[1,2-a]pyridin-3-yl)piperidine Di-TFA Salt

[0751] Step A:1-(t-Butoxycarbonyl)-4-(imidazo[1,2-a]pyridin-3-yl)piperidine

[0752] To a solution of 1.15 g of1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure23, Step C) in 15 mL ethanol was added 388 mg of 2-aminopyridine. Afterrefluxing for 18 h, the solvent was evaporated. The mixture waspartitioned between ethyl acetate and saturated sodium bicarbonatesolution. Aqueous layer was extracted with ethyl acetate (3×). Thecombined organic phase was washed with brine, dried over magnesiumsulfate and concentrated. The residue was purified by flashchromatography with 50% ethyl acetate in hexanes, followed by 100% ethylacetate to give 401 mg of the title compound as a solid.

[0753]¹H NMR (500 MHz, CDCl₃) δ 1.48 (s, 9H), 1.70 (m, 2H), 2.06 (d,J=13 Hz, 2H), 2.93-3.02 (m, 3H), 4.26 (br, 2H), 6.87 (t, J=6.8 Hz, 1H).7.21(m, 1H), 7.44(s, 1H), 7.69(d, J=9.2 Hz, 1H), 7.99 (d, J=6.9 Hz, 1H).

[0754] Step B: 4-Imidazo[1,2-a]pyridin-3-yl)piperidine Di-TFA Salt

[0755] To 100 mg of1-(t-butoxycarbonyl)-4-(imidazo[1,2-a]pyridin-3-yl)piperidine from StepA was added 2 mL TFA. The reaction was stirred at rt for 1 h. Themixture was concentrated under reduced pressure to afford 180 mg of aviscous oil.

Procedure 28

[0756] 4-(7-t-Butylimidazo[1,2-a]pyridin-3-yl)piperidine, TFA Salt

[0757] Step A: 2-Amino-4-t-butylpyridine

[0758] To 790 mg of sodium amide were added 20 mL of N,N-dimethylanilineand 2.74 g of 4-t-butyl pyridine at rt. The mixture was stirred at 150°C. for 6 h. During this period, 3 more portions of sodium amide (790 mgeach) were added. The reaction was cooled down to rt. The mixture waspartitioned between ethyl acetate and water. Aqueous layer was extractedwith ethyl acetate (3×). The combined organic phase was washed withbrine, dried over magnesium sulfate and concentrated. The residue waspurified by flash chromatography with 50% ethyl acetate in hexanesfollowed by 100% ethyl acetate to give 1.68 g of the title compound as asolid: ¹H NMR (500 MHz, CDCl₃) δ 1.21 (s, 9H), 6.44 (t, 1H), 6.6.62 (dd,J=5.5 Hz and, 1H), 7.94 (d, J=5.5 Hz, 1H).

[0759] Step B:1-(t-Butoxycarbonyl)-4-(7-t-butylimidazo[1,2-a]pyridin-3-yl)piperidine

[0760] The title compound was prepared from 470 mg of1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure23, Step C) and 277 mg of 2-amino-4-t-butyl pyridine (from Step A) in 12mL ethanol using a procedure analogous to that described in Example 235, Step A to provide 130 mg of the title compound as a solid.

[0761] Step C: 4-(7-t-Butylimidazo[1,2-a]pyridin-3-yl)piperidine, TFASSalt

[0762] The title compound was prepared from 35 mg of1-(t-butoxycarbonyl)-4-((7-t-butyl)imidazo[1,2-a]pyridin-3-yl)piperidine(from Step B) in 2 mL of TFA, using a procedure analogous to thatdescribed in Procedure 27, Step B to provide 60 mg of the title compoundas a viscous oil.

Procedure 29

[0763]4-(2-Ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)piperidine,Acetic Acid Salt

[0764] Step A: 2-Ethyl-imidazo[1,2-a]pyridine

[0765] The title compound was prepared from 2-aminopyridine and1-bromo-2-butanone, employing procedures analogous to those described inProcedure 27 Step A.

[0766]¹H NMR (500 MHz, CDCl₃): δ 1.34 (t, J=7.3 Hz, 3H), 2.82 (q, J=7.6Hz, 2H), 6.70 (t, J=6.6 Hz, 1H), 7.10 (m, 1H), 7.32 (s, 3H), 7.51 (d,J=8.9 Hz, 1H), 8.03 (dd, J=6.6, 0.9 Hz, 1H).

[0767] Step B: 3-Bromo-2-ethyl-imidazo[1,2-a]pyridine

[0768] To a solution of 2-ethyl-imidazo[1,2-a]pyridine (2.17 g, 14.9mmol) in ethanol (25 mL) was added bromine (2.0 g, 12.5 mmol) in water(5 mL) dropwise at rt. After stirring at rt for 4h, ethanol wasevaporated under reduced pressure. The residue was basified with aqueoussodium bicarbonate and extracted with methylene chloride (3×). Theorganic phase was washed with brine and dried over anhydrous magnesiumsulfate. Concentration followed by flash chromatography eluting with 20% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanesafforded the title compound (1.88 g) as a viscous oil.

[0769]¹H NMR (500 MHz, CDCl₃): δ 1.36 (t, J=7.5 Hz, 3H), 2.83 (q, J=7.6Hz, 2H), 6.88 (t, J=6.8 Hz, 1H), 7.20 (m, 1H), 7.55 (dd, J=8.9, 0.9 Hz,1H), 8.05 (dd, J=6.9, 1.2 Hz, 1H).

[0770] Step C: 2-Ethyl-3-(4-pyridyl)-imidazo[1,2-a]pyridine

[0771] To a solution of 3-bromo-2-ethyl-imidazo[1,2-a]pyridine (1.4 g,6.28 mmol), 4-tributylstannylpyridine (2.31 g, 6.28 mmol) and Pd (II)(Ph₃P)₂Cl₂ (442 mg, 0.63 mmol) in toluene (5 mL) was added lithiumchloride (26.7 mg, 0.63). After refluxing for 18 h, the mixture waspartitioned between ethyl acetate and aqueous sodium bicarbonate. Theaqueous layer was extracted with ethyl acetate (3×). Combined organicphase was washed with brine and dried over anhydrous magnesium sulfate.Concentration followed by flash chromatography eluting with 100% ethylacetate, then 10% methanol in methylene chloride afforded the titlecompound (543 mg) as a viscous oil.

[0772]¹H NMR (500 MHz, CDCl₃): δ 1.36 (t, J=7.5 Hz, 3H), 2.84 (q, J=7.5Hz, 2H), 6.68 (dt, J=6.8, 1.1 Hz, 1H), 7.21 (m, 1H), 7.39 (dd, J=5.9,1.6 Hz, 2H), 7.61 (dd, J=8.9, 1.0 Hz, 1H), 8.75 (d, J=5.9 Hz, 2H).

[0773] Step D:4-(2-Ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)piperidine,Acetic Acid Salt

[0774] A solution of 2-ethyl-3-(4-pyridyl)-imidazo[1,2-a]pyridine (700mg, 3.13 mmol) in ethanol (12 mL) and acetic acid (4 mL) washydrogenated using Platinum (IV) oxide (40 mg) under 40 psi of H₂ gas ina Parr shaker at rt for 18 h. The mixture was filtered through celiteand concentrated to give the title compound (1.47 g) as a viscous oil.

Procedure 30

[0775] 4-(2-Benzyloxazol-5-yl)piperidine

[0776] Step A: 1-Benzoylisonipecotic Acid

[0777] To a solution of 10 g of isonipecotic acid in 100 mL of water wasadded 31 mL of 5 N NaOH at 0° C. The reaction was warmed to roomtemperature and stirred for 0.5 h. The reaction was again cooled to 0°C. and 11.97 g of benzoyl chloride was added. The reaction was thenwarmed to room temperature and stirred for 1.5 h. Concentrated HCl wasthen added until a precipitate formed. The mixture was extracted with3×150 mL of ethyl acetate and the combined organic layers were driedover magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was dissolved in methylene chloride. Ether wasthen slowly added to precipitate the product which was filtered to give8 g of the title compound.

[0778]¹H NMR (500 MHz) 1.83 (m, 3H), 2.10 (m, 1H), 2.65 (m, 1H), 3.12(m, 2H), 3.79 (m, 1H), 4.53 (m, 1H), 7.38 (m, 5H).

[0779] Step B: 4-Hydroxymethyl-1-benzoylpiperidine

[0780] To a solution of 2 g of 1-benzoylisonipecotic acid (Step A) in 50mL THF at 0° C. were added 1.47 g of triethylamine and 1.99 g ofisobutyl chloroformate. The reaction was stirred for 1 h at 0° C. To asolution of 1.10 g of sodium borohydride in 30 mL DMF at 0° C. wasslowly added the above THF mixture. The reaction was again stirred for 1h at 0° C. Water (80 mL) was slowly added to the reaction and themixture was extracted 5×80 mL ethyl acetate and the combined organiclayers were dried over magnesium sulfate. The solvent was thenevaporated under reduced pressure. The residue was purified by flashchromatography with 1:1 hexane:ethyl acetate followed by hexane: ethylacetate: methanol, 50:50:5 to give 1.865 g of the title compound.

[0781] ESI-MS 219.9 (M+H); HPLC A: 2.34 min. (65148-258)

[0782] Step C: 1-Benzoylpiperidine-4-carboxaldehyde

[0783] To 1.99 g of dimethyl sulfoxide in 45 mL methylene chloride at−78° C. was added 2.16 g of oxalyl chloride. After 10 min, 1865 g of4-hydroxymethyl-N-benzoylpiperidine (Step B) in 15 mL of methylenechloride was added at −78° C. and stirred for 30 min. DIEA (5.49 mL) wasadded and this mixture was stirred for an additional 30 min. at −78° C.and then warmed to room temperature and stirred another 30 min. Thereaction was quenched with 50 mL water and extracted with 3×50 mLmethylene chloride. The combined organic layers were dried overmagnesium sulfate and evaporated under reduced pressure. The residue waschromatographed with 2:1 hexane:ethyl acetate followed by 1:1hexane:ethyl acetate to give 1.445 g of the title compound.

[0784]¹H NMR (500 MHz) 1.72 (m, 2H), 1.90 (m, 1H), 2.14 (m, 1H), 2.58(m, 1H), 3.21 (m, 2H), 3.68 (m, 1H), 4.41 (m, 1H), 7.39 (m, 5H), 9.72(m, 1H).

[0785] Step D: 4-(1-Hydroxy-prop-2-enyl)-1-benzoyl Piperidine

[0786] To a solution of 500 mg of 1-benzoylpiperidine-4-carboxaldehyde(Step C) in 10 mL THF at −78° C., was added 2.99 mmol of vinyl magnesiumbromide. The solution was warmed to 0° C. and stirred for 1 h. Thereaction was quenched with 15 mL of aq. ammonium chloride and extractedwith 3×20 mL ether and the combined organic layers were dried overmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by flash chromatography with 2:1 hexane: ethylacetate followed by 1:1 hexane:ethyl acetate followed by hexane: ethylacetate : methanol, 50:50:5 to give 411 mg of the title compound.

[0787]¹H NMR (500 MHz) 1.31 (m, 2H), 1.74 (m, 5H), 2.69 (m, 1H), 2.92(m, 1H), 4.80 (m, 1H), 3.68 (m, 1H), 5.22 (dd, 2H), 5.84 (m, 1H), 7.43(m, 5H).

[0788] Step E: 4-(1-Phenylacetyoxy-prop-2-enyl)-1-benzoylpiperidine

[0789] To 264 mg of 4-(1-hydroxy-prop-2-enyl)-1-benzoylpiperidine (StepD) in 5 mL DMF was added 220 mg of phenyl acetic acid, 292 mg of1-hydroxybenzotriazole, 414 mg of EDC, and 419 mg of DIEA. The reactionwas stirred at room temperature overnight. The solution was diluted with50 mL of ether and washed with 2×40 mL water. The aqueous layers werethen extracted with 2×50 mL ether and the combined organic layers weredried over magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by flash chromatography with 4:1hexane: ethyl acetate followed by 2:1 hexane:ethyl acetate to give 123mg of the title compound.

[0790] ESI-MS 364.1 (M+H).

[0791] Step F: 1-Benzoyl-4-(2-benzyloxazol-5-yl)piperidine

[0792] Ozone was bubbled through a solution of 120 mg of4-(1-phenylacetyoxy-prop-2-enyl)-1-benzoylpiperidine (Step E) in 8 mLmethylene chloride at −78° C. until the reaction turned blue. To thissolution 205 mg of methyl sulfide was added and the reaction was stirredat room temperature overnight. The solvent was evaporated under reducedpressure to give 121 mg of the residue. This residue was dissolved in 3mL of acetic acid and 76 mg of ammonium acetate was added. The reactionwas stirred at 110° C. for 2.5 h, 20 mL of water was added and themixture was extracted with 3×20 mL methylene chloride. The combinedorganic layers were dried over magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by flashchromatography with 2:1 hexane:ethyl acetate followed by 1:1hexane:ethyl acetate followed by hexane: ethyl acetate:methanol, 50:50:5to give 40 mg of the title compound.

[0793] ESI-MS 347.0 (M+H); HPLC A: 3.68 min.

[0794] Step G: 4-(2-Benzyloxazol-5-yl)piperidine

[0795] To 40 mg of 1-benzoyl-4-(2-benzyloxazol-5-yl)piperidine (step F)in 4.5 mL methanol and 0.5 mL water was added 260 mg of potassiumhydroxide. The reaction was stirred at 80° C. overnight, 20 mL of waterwas added and the mixture was extracted with 3×20 mL ethyl acetate. Thecombined organic layers were dried over magnesium sulfate. The solventwas evaporated under reduced pressure to give 22 mg of the titlecompound.

[0796] ESI-MS 242.9 (M+H); HPLC A: 2.29 min.

Procedure 31

[0797] 4-(2-Benzyl-1,3-imidazol-5-yl)piperidine

[0798] Step A: 4-Bromoacetyl-1-(t-butoxycarbonyl)piperidine

[0799] To a freshly prepared solution of LDA (from diisopropylamine(0.61 g, 6.0 mmol) and n-butyl lithium (2.2 mL, 2.5 M sol'n. In hexane)in 10 mL THF at −78° C. was added a solution of4-acetyl-1-(t-butoxycarbonyl) piperidine (1.0 g, 4.7 mmol) in 2.0 mL THFand the resultant mixture was stirred for 20 min. A mixture oftrimethylsilyl chloride and triethylamine (1.37 mL, 10.8 mmol and 2.16mL, 15.5 mmol) was added and the reaction mixture was gradually warmedto rt and stirred for an additional 1 h. All the volatile were removedand the crude silyl enol ether was dissolved in 10 mL of THF and themixture was cooled to 0° C. To this mixture was added in successionpropylene oxide (1.0 mL) and NBS (1.0 g) and the mixture was stirred for15 min, quenched with a saturated sodium bicarbonate followed byextraction with methylene chloride. The methylene chloride layer waswashed with brine, dried, evaporated and purified by silica columnchromatography. Elution with methylene chloride and ether (19:1) gavethe title compound (1.11 g) as a yellow solid.

[0800]¹HNMR (500 MHz, CDCl₃): δ 4.16 (s, 2H), 4.12 (m, 2H), 2.79-2.84(m, 3H), 1;47 (s, 3H).

[0801] Step B:4-(2-(2,6-Dichlorobenzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine

[0802] A mixture of the bromo compound (0.4 g, 1.36 mmol) from Step Aand 2,6-dichlorophenylacetamidine (0.55 g, 2.7 mmol) in 30 mL ofchloroform was refluxed for 4 h. The reaction mixture was filtered. Thefiltrate was evaporated and purified by silica column chromatography.Elution with hexane:ethyl acetate:methanol 49:49:2 gave (0.28 g) of thetitle compound.

[0803]¹HNMR (500 MHz, CDCl₃): δ 7.35-7.15 (m, 3H), 6.55 (s, 1H), 4.45(s, 2H), 4.14 (br, 2H), 2.81-2.69 (m, 3H), 1.46 (s, 3H).

[0804] Step C:4-((2-Benzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine

[0805] A mixture of4-(2-(2,6-dichlorobenzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine(0.51 g, 1.24 mmol) from Step B, Pd/C (0.13 g) and ammonium formate (1.5g, 24.8 mmol) in 8 mL of methanol was refluxed for 30 min. The reactionmixture was filtered and the filtrate was evaporated. The residue waspartitioned between methylene chloride and water (200 mL). The methylenechloride layer was washed with brine, dried, evaporated and purified bysilica column chromatography. Elution with 3% methanol-methylenechloride gave (0.35 g) of the title compound.

[0806]¹HNMR (500 MHz, CDCl₃): δ 7.34-7.22 (m, 5H), 6.58 (s, 1H), 4.18(br, 2H), 4.08 (s, 2H), 2.71 (br, 2H), 2.68 (m, 1H), 1.47 (s, 3H).

[0807] Step D: 4-(2-Benzyl-1,3-imidazol-5-yl)piperidine Hydrochloride

[0808] To 4-((2-benzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine (0.16 g) from Step C in 2 mL of ethyl acetate at 0° C. wasadded a 2 mL saturated solution of HCl in ethyl acetate. The reactionmixture was stirred for 30 min. Evaporation of ethyl acetate followed bytrituration of the resultant oil gave (0.15 g) of the title compound.

[0809]¹HNMR (500 MHz, CD₃OD): δ 7.40-7.29 (m, 6H), 4.32 (s, 2H), 3.49(m, 2H), 3.31-3.01 (m, 3H), 2.24 (m, 2H), 1.92 (m, 2H).

Procedure 32

[0810] 4-((2-Benzyl-4-ethyl)-1,3-imidazol-5-yl)piperidine

[0811] Step A:4-((2-Benzyl-4-iodo)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine

[0812] To a mixture of4-((2-benzyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine (0.15 g,0.43 mmol). Iodine (0.16 g, 0.65 mmol) and potassium iodide (0.22 g, 1.3mmol) in 4 mL THF:water (1:1) was added a solution of sodium hydroxide(0.5 mL) and stirred at rt for 30 min. After confirming the completionof reaction by TLC, the reaction was quenched with a saturated solutionof sodium thiosulfate and the pH was adjusted to 7-8. The resultantmixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with brine, dried, evaporated and purified by silica columnchromatography. Elution with 1% methanol-methylene chloride gave (0.17g) of the title compound.

[0813]¹HNMR (500 MHz, CDCl₃): δ 7.32-7.22 (m, 5H), 4.13 (br, 2H), 4.06(s, 2H), 2.74 (m, 3H), 1.47 (s, 3H).

[0814] Step B:4-((2-Benzyl-4-ethenyl)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine

[0815] A mixture of4-((2-benzyl-4-iodo)-1,3-imidazol-5-yl)-1-(t-butoxycarbonyl)piperidine(0.17 g, 0.36 mmol) from Step A, tri-n-butyl vinyltin (0.17 g, 0.54mmol) and tetrakistriphenylphosphinyl palladium (0.020 g) in 4 mLtoluene was stirred at 100-110° C. until the completion of reaction byTLC. Evaporation of the volatiles followed by purification by silicacolumn and elution with 1% methanol-methylene chloride gave (0.061 g) ofthe title compound.

[0816]¹HNMR (500 MHz, CDCl₃): δ 7.36-7.26 (m, 5H), 6.61-6.55 (m, 1H),5.10 (m, 2H), 4.33 (br, 2H), 4.13 (s, 2H), 1.47(s, 3H).

[0817] Step C:4-((2-Benzyl-4-ethyl)-1,3-imidazol-2-yl)-1-(t-butoxycarbonyl)piperidine

[0818] A mixture of4-((2-benzyl-4-ethenyl)-1,3-imidaz-5-yl)-1-(t-butoxycarbonyl)piperidine(0.073 g) from Step B in 3.0 mL methanol was hydrogenated over Pd/C (5mg) at rt. Evaporation of the volatiles followed by purification bypreparative silica chromatography and elution with 1% methanol-methylenechloride gave (0.043 g) of the title compound.

[0819]¹HNMR (500 MHz, CDCl₃): δ 7.31-7.20 (m, 5H), 4.19 (br, 2H), 4.01(s, 2H), 2.74-2.66 9m, 3H), 2.51 (q, 2H), 1.46(s, 3H), 1.15 (t, 3H).

[0820] Step D: 4-((2-Benzyl-4-ethyl)-1,3-imidazol-2-yl)piperidineDi-Hydrochloride

[0821] To4-((2-benzyl-4-ethyl)-1,3-imidazol-2-yl)-1-(t-butoxycarbonyl)piperidine(0.043 g) from Step C in 1.0 mL ethyl acetate at 0° C. was added a 2.0mL saturated solution of HCl in ethyl acetate. The reaction mixture wasstirred for 30 min. Evaporation of ethyl acetate followed by triturationof the resultant oil gave (0.038 g) of the title compound.

Procedure 33

[0822] 4-(2-Ethyl-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)-1-piperidine

[0823] Step A: (1-Benzylpiperidin-4-yl)-(cyclohexanon-2-yl)ketone

[0824] To a suspension of 1.60 g 60% sodium hydride in 10 mL dry THF wasadded a solution of 1.963 g (20 mmole) cyclohexanone and 9.893 g (40mmole) of 1-benzylpiperidine-4-carboxylic acid ethyl ester in 30 mL THF.This mixture was heated to reflux over night. Work-up followed by silicagel FC (15-50% ethyl acetate in hexanes with 1% triethylamine) provided4.4 g product containing about 5.7:1 molar ratio of starting1-benzylpiperidine-4-carboxylic acid ethyl ester and title compound.

[0825] ESI-MS 300.3 (M+H), HPLC A: 2.90 and 3.57 min. (for tautomericforms).

[0826] Step B:4-(2-Ethyl-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)-1-benzylpiperidine

[0827] The title compound was prepared from the semi-crude(1-benzylpiperidin-4-yl)-(cyclohexanon-2-yl)ketone from step A and 34%aqueous ethylhydrazine in 4:1 acetonitrile and water at roomtemperature. This provided 8:1 ratio of isomeric ethyl pyrazoles infavor of the title compound. (Note: Use of ethyl hydrazine oxalate inthe presence of DIEA gave about 2:1 ratio of the same isomers.) The1-benzylpiperidine-4-carboxylic acid ethyl ester present in the startingβ-diketone was removed after saponification of the crude product withsodium hydroxide in water ethanol mixture flowed by extractive work-up.The desired ethyl isomer is the higher R_(f) isomer. It was isolated onsilica gel chromatography (60˜100% ethyl acetate in hexanes and 5˜20%methanol in ethyl acetate, both with 1% triethylamine).

[0828]¹H NMR (500 MHz) δ 7.33-7.36 (m, 4H), 7.26˜7.30 (m, 1H), 4.07 (q,7.2 Hz, 2H), 3.57 (s, 2H), 3.00˜3.03 (m, 2H), 2.64˜2.66 (m, 2H),2.60-2.63 (m, 2H), 2.57-2.63 (m, 1H), 1.96-2.08 (m, 4H), 1.69-1.81 (m,6H), 1.39 (t, 7.2 Hz, 3H). The identity of the title compound wasconfirmed by NOE difference spectroscopy.

[0829] Step C:4-(2-Ethyl-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)piperidine

[0830] A mixture of 0.273 g4-(2-ethyl-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)-1-benzylpiperidine fromStep B above, 0.789 g ammonium formate, and 35 mg 20% Pd(OH)₂ in 6 mLmethanol was heated at 65° C. for 1 h. Basic aqueous work-up with etherextraction provided 0.192 g title compound as a colorless solid (97%).

[0831]¹H NMR (500 MHz) δ 4.08 (q, 7.2 Hz, 2H), 3.19 (br d, 11.9 Hz, 2H),2.71˜2.77 (m, 1H), 2.68˜2.74 (m, 2H), 2.64˜2.66 (m, 2H), 2.60˜2.62 (m,2H), 1.82˜1.91 (m, 2H), 1.71˜1.80 (m, 6H), 1.40 (t, 7.2 Hz, 3H). Theidentity of the title compound was confirmed again by NOE differencespectroscopy.

Procedure 34

[0832] 4-(4,5,6,7-Tetrahydro-(2H)-indazol-3-yl)-1-piperidine

[0833] Step A: 4-(4,5,6,7-Tetrahydro-(2H)-indazol-3-yl)-1-benzylpiperidine, Trifluoroacetic Acid Salt

[0834] The title compound was prepared using a procedure similar to thatin Procedure 33, Step B with hydrazine instead of ethyl hydrazine. Itwas further purified on HPLC.

[0835]¹H NMR (500 MHz, CD₃OD) δ 7.47˜7.55 (m, 5H), 4.35 (s, 2H), 3.61(br d, 12.3 Hz, 2H), 3.13˜3.21 (m, 3H), 2.71˜2.73 (m, 2H), 2.56˜2.58 (m,2H), 2.17 (br d, 13.3 Hz, 2H), 2.04˜2.12 (m, 2H), 1.79˜1.89 (m, 4H).ESI-MS 296.3 (M+H), HPLC A: 2.33 min.

[0836] Step B: 4-(4,5,6,7-Tetrahydro-(2H)-indazol-3-yl)piperidine

[0837] The title compound was prepared using a procedure similar to thatin Procedure 33, Step C as a white solid.

[0838]¹H NMR (500 MHz) δ 3.20 (br d, 12.4 Hz, 2H), 2.72˜2.797 (m, 3H),2.64˜2.66 (m, 2H), 2.49˜2.52 (m, 2H), 1.87˜1.90 (m, 2H), 1.70˜1.84 (m,6H). ESI-MS 206.2 (M+H), HPLC A: 0.80 min.

Procedure 35

[0839] 3,3-Difluoro-3-(2-pyridyl)propyl)piperidine

[0840] Step A: Ethyl oxo(2-pyridyl)acetate

[0841] A solution of n-butyl lithium (100 mL, 1.6 M, 160 mmol) inhexanes was added over 2 min. to a stirred solution of 2-bromopyridine(15.0 mL, 24.9 g, 157 mmol) in 500 mL of ether cooled in a dryice/isopropanol bath, causing a temporary rise in temperature to −47° C.After 25 min., the solution was transferred rapidly to a stirred 0° C.solution of diethyl oxalate (75 mL, 81 g, 550 mmol) in 1000 mL of ether.After 2 h at 0° C., the mixture was washed with saturated aq. sodiumbicarbonate (900 mL), water (900 mL), and saturated aq. brine (450 mL).The organic layer was dried (magnesium sulfate), filtered, andevaporated. Distillation gave the title compound as 11.68 g of yellowliquid, B.p. 96-108° C. (0.3 mm Hg pressure). For the title compound:

[0842]¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=5, 1H), 8.13 (d, J=8, 1H),7.93 (td, J=8, 2, 1H), 7.56 (ddd, J=8, 5, 1, 1H), 4.51 (q, J=7, 2H),1.44 (t, J=7, 3H).

[0843] Step B: Ethyl difluoro(2-pyridyl)acetate

[0844] Ethyl oxo(2-pyridyl)acetate (11.59 g, 64.7 mmol, from Procedure35, Step A) was added to a flask containing (diethylamino)sulfurtrifluoride (18.0 mL, 22.0 g, 136 mmol) and the solution was heated to45° C. overnight. An additional portion of (diethylamino)sulfurtrifluoride (24.9 g, 154 mmol) was added and the solution was heated to55° C. for 2 days. After cooling to rt, the solution was added carefullyto a stirred mixture of ethyl acetate (600 mL), ice (500 g), water (500mL), and sodium bicarbonate (100 g). After the resulting reaction hadsubsided, the layers were separated and the organic layer was washedwith 250 mL each of saturated aq. sodium bicarbonate, water, andsaturated aq. brine. The organic layer was dried (sodium sulfate),decanted, and evaporated. Distillation gave 8.45 g of yellow liquid,B.p. 50-63° C. (0.1 mm Hg), containing a residual impurity. Furtherpurification by flash column chromatography on silica gel, eluting with80:20 v/v to 75:25 v/v hexanes/ethyl acetate, gave the title compound as6.54 g of yellow oil. For the title compound:

[0845]¹H NMR (500 MHz, CDCl₃) δ 8.68 (d, J=5, 1H), 7.88 (td, J=8, 2,1H), 7.76 (d, J=8, 1H), 7.44 (dd, J=8, 5, 1H), 4.40 (q, J=7, 2H), 1.35(t, J=7, 3H).

[0846] Step C:1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-en-1-yl)piperidine

[0847] Ethyl difluoro(2-pyridyl)acetate (1.00 g, 4.97 mmol, fromProcedure 35, Step B) was dissolved in CH₃OH (15 mL) in a 3-neck roundbottom flask fitted with a mechanical stirrer, and the resultingsolution was cooled in a dry ice/isopropanol bath. Sodium borohydride(114 mg, 3.0 mmol) was added in 2 portions 15 min. apart. After anadditional 55 min., the cold reaction was quenched by the addition ofsaturated aq. ammonium chloride (6.5 mL) over 12 min. After 10 min., thecooling bath was removed and the mixture was stirred for 35 min. beforebeing diluted with saturated aq. brine (100 mL) and extracted with ethylacetate (4×75 mL). The combined organic layers were dried (sodiumsulfate), decanted, and evaporated to give 1.02 g of crude2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol as an amber oil.

[0848] A suspension of((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide(5.29 g, 9.00 mmol, from Procedure 17, Step C) in THF (70 mL) wasstirred at rt for 40 min. A toluene solution of potassiumbis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving anorange suspension. After 40 min., crude2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) wasadded in THF (20 mL). After an additional 50 min., the mixture wasquenched by the addition of saturated aq. NH₄Cl (10 mL). The mixture waspartitioned between ethyl acetate (100 mL) and water (100 mL), and theaqueous layer was extracted with ethyl acetate (3×100 mL). The organiclayers were washed in succession with saturated aq. brine (100 mL),dried (sodium sulfate), decanted, and evaporated. Purification by flashcolumn chromatography on silica gel, eluting with 90:10 v/v to 80:20 v/vhexanes/ethyl acetate, gave 1.18 mg of the title compound (approximately95:5 cis/trans mixture) as an oil which solidified upon standing. Forthe title compound:

[0849]¹H NMR (500 MHz, CDCl₃) δ 8.68 (d, J=5, 1H), 7.84 (td, J=8, 2,1H), 7.70 (d, J=8, 1H), 739 (dd, J=8,5, 1H), 5.93 (td, J=14, 11, 1H),5.70 (ddt, J=11, 10,2, 1H), 4.17-3.99 (bs, 2H), 2.80-2.62 (m, 3H), 1.58(d, J=12, 2H), 1.46 (s, 9H), 1.26 (qd, J =12, 4, 2H).

[0850] ESI-MS 339 (M+H); HPLC A: 4.28 min.

[0851] Step D:1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)propyl)piperidine

[0852] Potassium azodicarboxylate (246 mg, 1.27 mmol) was added to astirred solution of1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-enyl)piperidine(143 mg, 0.42 mmol, from Procedure 35, Step C) in methanol (1.4 mL) atrt. A solution (0.58 mL) of 75:25 v/v CH₃OH/AcOH was added in threeportions at 30-min. intervals. After two h, an additional portion ofpotassium azodicarboxylate (246 mg, 1.27 mmol) was added, followed by asolution (0.58 mL) of 75:25 v/v CH₃OH/AcOH added in three portions at30-min. intervals. After another two h, a third portion of potassiumazodicarboxylate (246 mg, 1.27 mmol) was added, followed by a solution(0.58 mL) of 75:25 v/v CH₃OH/AcOH added in the same manner as before.After stirring overnight, the mixture was diluted with ethyl acetate (50mL) and washed with saturated aq. sodium bicarbonate (30 mL) followed bysaturated aq. brine (30 mL). The organic layer was dried (sodiumsulfate), decanted, and evaporated to give the crude product containingapproximately 30% starting olefin. This material was combined with crudeproduct similarly obtained from1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-enyl)piperidine(20 mg, 0.059 mmol) and purified by preparative HPLC on a 20×250 mmChiracel OD column, eluting with 98:2 v/v hexanes/isopropanol, to give105 mg of the title compound:

[0853]¹H NMR (500 MHz, CDCl₃) δ 8.68 (d, J=5, 1H), 7.82 (td, J 8, 2,1H), 7.64 (d, J=8, 1H), 7.38 (dd, J=8, 5, 1H), 4.17-4.00 (bs, 2H),2.75-2.62 (m, 2H), 2.42-2.30 (m, 2H), 1.67 (d, J=12, 2H), 1.46 (s. 9H),1.45-1.38 (m, 3H), 1.15-1.04 (m, 2H).

[0854] ESI-MS 241 (M+H-100); HP-LC A: 4.36 min.

[0855] Step E: 4-(3,3-Difluoro-3-(2-pyridyl)propyl)piperdine

[0856] The title compound was prepared using procedures analogous tothose described in Procedure 17, Step H, substituting1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)propyl)piperidine(from Procedure 35, Step D) for1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperidine.For the title compound:

[0857]¹H NMR (500 MHz, CD₃OD) δ 8.62 (d, J=5, 1H), 7.95 (td, J=8, 2,1H), 7.68 (d, J=8, 1H), 7.50 (dd, J=8, 5, 1H), 2.99 (d, J=12, 2H), 2.53(td, J=12, 3, 2H), 2.37-2.26 (m, 2H), 1.67 (d, J=12, 2H), 1.42-1.28 (m,3H), 1.08 (dq, J=12, 4, 2H); ESI-MS 241 (M+H); HPLC A: 2.21 min.

Procedure 36

[0858] 4-(3,3-Difluoro-3-(6-methylpyridazin-3-yl)propyl)piperidine

[0859] Step A: 3-Bromo-6-methylpyridazine

[0860] A solution (3.0 mL) containing 30%HBr in acetic acid was added to3-(trifluoromethanesulfonyloxy)-6-methylpyridazine (prepared asdescribed by M. Rohr, et al., Heterocycles, 1996, 43, 1459-64) and themixture was heated in a 100° C. oil bath for 2.5 h. The mixture wascooled in an ice bath, adjusted to pH≧9 (as determined using pH paper)by the careful addition of 20% aqueous NaOH, and extracted with ether(3×20 mL). The organic layers were dried (sodium sulfate), decanted, andevaporated to give title compound as 359 mg of pale tan crystals. Forthe title compound:

[0861]¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, J=9, 1H), 7.22 (d, J=9, 1H),2.70 (s, 3H).

[0862] Step B: Ethyl difluoro(6-methylpyridazin-3-yl)acetate

[0863] This procedure is derived from the general method of T. Taguchi,et al. (Tetrahedron Lett., 1986, 27, 6103-6106). Ethyldifluoroiodoacetate (0.355 mL, 651 mg, 2.60 mmol) was added to a rapidlystirred suspension of copper powder (333 mg, 5.24 mmol) in DMSO (6.5 mL)at rt. After 50 min., 3-bromo-6-methylpyridazine (300 mg, 1.73 mmol) wasadded in DMSO (1.0 mL). After 20 h, the mixture was transferred to aseparatory funnel containing water (25 mL) and saturated aq. NH₄Cl (25mL), and extracted with ethyl acetate (2×50 mL). The organic extractswere washed with saturated aq. brine, dried (sodium sulfate), decanted,and evaporated. Purification by flash column chromatography on silicagel, eluting with 70:30 v/v hexanes/ethyl acetate, gave 363 mg of thetitle compound as an amber liquid. For the title compound:

[0864]¹H NMR (500 MHz, CDCl₃) δ 7.79 (d, J=9, 1H), 7.53 (d, J=9, 1H),4.43 (q, J=7, 2H), 2.82 (s, 3H), 1.38 (t, J=7, 3H).

[0865] Steps C-E:4-(3,3-Difluoro-3-(6-methylpyridazin-3-yl)propyl)piperidine

[0866] The title compound was prepared using procedures analogous tothose described in Procedure 35, Steps C-E, substituting ethyldifluoro(6-methylpyridazin-3-yl)acetate (from Procedure 36 Step B) forethyl difluoro(2-pyridyl)acetate in Step C. For the title compound:

[0867]¹H NMR (500 MHz, CD₃OD) δ 7.86 (d, J=9, 1H), 7.74 (d, J=9, 1H),2.99 (dm, J=12, 2H), 2.74 (s, 3H), 2.54 (td, J=12, 3, 2H), 2.51-2.40 (m,2H), 1.69 (bd, J=12, 2H), 1.47-1.34 (m, 3H), 1.10 (qd, J=12, 4, 2H).

Procedure 37

[0868]4-(3,3-Difluoro-3-(5-(trifluoromethyl)pyrid-2-yl)propyl)piperidine

[0869] The title compound was prepared using procedures analogous tothose described in Procedure 36, substituting2-bromo-5-(trifluoromethyl)pyridine for 3-bromo-6-methylpyridazine inStep B. For the title compound:

[0870]¹H NMR (500 MHz, CD₃OD) δ 8.96 (s, 1H), 8.28 (dd, J=8, 2, 1H),7.88 (d, J=8, 1H), 2.99 (bd, J=12, 2H), 2.53 (td, J=12, 2, 2H),2.43-2.31 (m, 2H), 1.68 (bd, J=13, 2H), 1.44-1.28 (m, 3H), 1.09 (qd,J=12, 3, 2H);

[0871] ESI-MS 309 (M+H); HPLC A: 2.32 min.

Procedure 38

[0872] 4-(3 ,3-Difluoro-3-(3-pyridyl)propyl)piperidine

[0873] Step A: Dimethyl (2-oxo-2-(3-pyridyl)ethyl)phosphonate

[0874] A solution of n-butyl lithium in hexanes (9.0 mL, 1.6 M, 14 mmol)was added over 10 min. to a solution of dimethyl methylphosphonate (1.50mL, 1.72 g, 13.8 mmol) in THF (60 mL) cooled in a dry ice/isopropanolbath. After 30 min., a solution of methyl nicotinate (757 mg, 5.52 mmol)in THF (6 mL) was added over 2 min. The solution was stirred in thecooling bath for 45 min. before being allowed to warm to 0° C. over 1 h.The reaction was quenched with saturated aq. NH₄Cl (50 mL) and thenpartitioned between saturated aq. brine (50 mL) and methylene chloride(200 mL). The aq. layer was extracted with methylene chloride (2×100mL). The combined organic layers were dried (sodium sulfate) decanted,and evaporated. Purification by flash column chromatography on silicagel, eluting with ethyl acetate followed by 97:3 v/v methylenechloride/CH₃OH, gave material containing some residual impurity. Furtherpurification by flash column chromatography on silica gel, eluting with50:50:5 v/v/v to 50:50:10 v/v/v toluene/ethyl acetate /CH₃OH gave 1.15 gof the title compound. For the title compound: ¹H NMR (500 MHz, CDCl₃) δ9.26-9.20 (bs, 1H), 8.83 (d, J=4, 1H), 8.34 (dt, J=8, 2, 1H), 7.70 (dd,J=8, 4, 1H), 3.82 (d, J=11, 6H), 3.67 (d, J=24, 2H).

[0875] Step B:1-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)prop-1-enyl)piperidine

[0876] 1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (750 mg,1.77 mmol) was added to a solution of1-(t-butoxycarbonyl)-4-(hydroxymethyl)piperidine (339 mg, 1.57 mmol,from Procedure 17, Step A) in methylene chloride (10 mL) and the mixturewas stirred at rt. After 45 min., and additional portion of1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (150 mg, 0.35mmol) was added. After an additional 30 min., ether (30 mL) and 1.3 NNaOH (10 mL) were added and stirring was continued for 20 min. Themixture was transferred to a separatory funnel with additional ether (30mL) and 1.3 N NaOH (15 mL). The organic layer was separated, washed withwater (20 mL), dried (sodium sulfate), decanted, and evaporated to give291 mg of 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde as a colorlessoil.

[0877] A solution of dimethyl (2-oxo-2-(3-pyridyl)ethyl)phosphonate (150mg, 0.65 mmol, from Procedure 38, Step A) in THF (1.8 mL) was added to astirred suspension of sodium hydride (60% oil dispersion, 15 mg ofsodium hydride, 0.63 mmol) in THF (3.0 mL). The resulting suspension waswarmed in a 45° C. oil bath for 30 min. After the mixture had cooled tort, 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde (112 mg, 0.53 mmol)was added in THF (1.5 mL). After stirring overnight at rt, the mixturewas diluted with ether (20 mL) and washed with 2.5 N NaOH (20 mL)followed by saturated aq. brine (20 mL). The aq. layers were extractedin succession with ether (20 mL), and the combined organic layers weredried (sodium sulfate), decanted, and evaporated. Purification by flashcolumn chromatography on silica gel, eluting with 80:20 v/v to 60:40 v/vhexanes/ethyl acetate, gave 135 mg of the title compound (trans isomer)as a yellow syrup. For the title compound: ¹H NMR (500 MHz, CDCl₃) δ9.17-9.13 (bs, 1H), 8.81 (bd, J=4, 1H), 8.27 (d, J=8, 1H), 7.49 (dd,J=8, 4, 1H), 7.07 (dd, J=15, 7, 1H), 6.85 (dd, J=15, 1, 1H), 4.25-4.13(bs, 2H), 2.87-2.78 (m, 2H), 2.51-2.41 (m, 1H), 1.83 (d, J=12, 2H), 1.49(s, 9H), 1.45 (qd, J=12, 4, 2H).

[0878] ESI-MS 261 (M+H-56), 217 (M+H-100); HPLC A: 1.73 min.

[0879] Step C:1-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)propyl)piperidine

[0880] 1-(t-Butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)prop-1-enyl)piperidine(940 mg, 2.97 mmol, from Procedure 38, Step B) was hydrogenated using 5%Pd/C in 95% ethanol at atmospheric pressure. Purification by flashcolumn chromatography on silica gel, eluting with 90:10 v/v to 50:50 v/vhexanes/ethyl acetate gave 884 mg of the title compound as a colorlesssyrup. For the title compound:

[0881]¹H NMR (500 MHz, CDCl₃) δ 9.23-9.15 (bs, 1H), 8.81 (bd, J=4, 1H),8.28 (dt, J =8, 1, 1H), 7.48 (dd, J=8, 4, 1H), 4.19-4.04 (bs, 2H), 3.04(t, J=8, 2H), 2.70 (bt, J=11, 2H), 1.78-1.70 (m, 4H), 1.56-1.45 (m, 1H),1.47 (s, 9H), 1.17 (qd, J=12, 4, 2H).

[0882] ESI-MS 263 (M+H-56), 219 (M+H-100); HPLC A: 1.78 min.

[0883] Step D:1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(3-pyridyl)propyl)piperidine

[0884] A solution of1-(t-butoxycarbonyl)-4-(3-oxo-3-(3-pyridyl)propyl)piperidine (810 mg,2.54 mmol, from Procedure 38, Step C) in (diethylamino)sulfurtrifluoride (3.30 mL, 3.66 g, 23 mmol) was stirred in a teflon tube at40° C. for 2 days. The reaction was diluted with methylene chloride (20mL) and the resulting solution was added in portions to a stirredmixture of water (150 mL), ice (150 g) and sodium bicarbonate (29.3 g).After the resulting reaction had subsided, the mixture was extractedwith ethyl acetate (2×200 mL). The organic layers were washed insuccession with saturated aq. brine (100 ML), dried (sodium sulfate),decanted, and evaporated. Flash column chromatography on silica gel,eluting with 80:20 v/v to 50:50 v/v toluene/ether, gave materialcontaining some residual impurity. Further purification by preparativeBPLC on a 20×250 mm Chiracel OD column, eluting with 80:20 v/vhexanes/isopropanol, gave 395 mg of the title compound:

[0885]¹H NMR (500 MHz, CD₃OD) δ 8.69 (s, 1H), 8.64 (d, J=5, 1H), 7.97(d, J=8, 1H), 7.54 (dd, J=8, 5, 1H), 4.04 (d, J=13, 2H), 2.78-2.62 (bs,2H), 2.31-2.20 (m, 2H), 1.68 (d, J=12, 2H), 1.50-1.40 (m, 1H), 1.43 (s,9H), 1.40-1.34 (m, 2H), 1.02 (qd, J=12, 4, 2H).

[0886] ESI-MS 285 (M+H-56), 241 (M+H-100); HPLC A: 2.10 min.

[0887] Step E: 4-(3,3-Difluoro-3-(3-pyridyl)propyl)piperidine

[0888] The title compound was prepared using procedures analogous tothose described in Procedure 17, Step H, substituting1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(3-pyridyl)propyl)piperidine(from Procedure 38, Step D) for1-(t-butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperidine.For the title compound:

[0889]¹H NMR (500 MHz, CD₃OD) δ 8.68 (s, 1H), 8.64 (d, J=4, 1H), 7.97(d, J=8, 1H), 7.54 (dd, J=8, 4, 1H), 2.98 (bd, J=12, 2H), 2.52 (td,J=12, 3, 2H), 2.30-2.18 (m, 2H), 1.66 (bd, J=13, 2H), 1.44-1.30 (m, 3H),1.08 (qd, J=12, 3, 2H); ESI-MS 241 (M+H).

Procedure 39

[0890] 4-(3,3-Difluoro-3-(1-methylpyrazol-4-yl)propyl)piperidine

[0891] The title compound was prepared using procedures analogous tothose described in Procedure 38, substituting ethyl1-methyl-4-pyrazolecarboxylate, obtained by methylation of ethyl4-pyrazolecarboxylate with iodomethane and K₂CO₃ in CH₃CN at rt, formethyl nicotinate in Step A. For the title compound:

[0892]¹H NMR (500 MHz, CD₃OD) δ 7.78 (s, 1H), 7.54 (s, 1H), 3.89 (s,3H), 3.00 (dt, J=12, 3, 2H), 2.55 (td, J=12, 3, 2H), 2.22-2.10 (m, 2H),1.69 (bd, J=12, 2H), 1.45-1.34 (m, 3H), 1.10 (qd, J=12, 4, 2H).

[0893] ESI-MS 244 (M+H, 60%), 224 (M-19, 100%); HPLC A: 0.98 min.

Procedure 40

[0894] 4-(7-Chloroimidazo[1,2-a]pyridin-3-yl)piperidine, TFA Salt

[0895] The title compound was prepared from 350 mg of1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure,Step C) and 162 mg of 2-amino-4-chloropyridine (prepared usingprocedures analogous to those described by R. J. Sundberg et al, Org.Preparations & Procedures Int. 1997, 29, (1), 117-122) in 10 mL ethanolusing a procedure analogous to that described in Procedure 27, Step A-Bto provide 240 mg of the BOC intermediate as a solid prior to the finalde-BOC to give the title TFA salt.

Procedure 41

[0896] 4-(7-n-Propylimidazo[1,2-a]pyridin-3-yl)piperidine, TFA Salt

[0897] The title compound was prepared according to the generalprocedures of Procedure 27 and 28, employing 2-amino-4-n-propylpyridine(prepared using a procedure analogous to that described in Procedure 28,Step A) in place of 2-aminopyridine in Procedure 27, Step A.

Procedure 42

[0898] 4-(6-Fluoroimidazo[1,2-a]pyridin-3-yl)piperidine, TFA Salt

[0899] The title compound was prepared from1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure23, Step B) and 2-amino-5-fluoropyridine (prepared using proceduresanalogous to those described by D. C. Baker et al, Synthesis. 1989, 905)using a procedures similar to that described in Procedure 27, Step A-C.

[0900] For the BOC intermediate:

[0901]¹H NMR (500 MHz, CDCl₃): δ 1.51 (s, 9H), 1.60-1.80 (m, 2H), 2.07(br d, 2H), 2.85-3.00 (m, 3H), 4.20-4.40 (br, 2H), 7.11 (m, 1H), 7.47(s, 3H), 7.60(m, 1H), 7.89 (m, 1H).

Procedure 43

[0902] 4-(6-Fluoro-7-methylimidazo[1,2-a]pyridin-3-yl)piperidine

[0903] The title compound was prepared using procedures analogous tothose described in Procedure 27, Step A-C, except2-amino-5-fluoro-4-methylpyridine (prepared using procedures analogousto those described by D. C. Baker et al, Synthesis. 1989, 905) wasemployed in place of 2-amino-5-fluoropyridine in Step A.

Procedure 44

[0904] 4-(2-Ethylindazol-3-yl)piperidine, TFA Salt

[0905] Step A: 2-Ethylindazole

[0906] To a solution of indazole (6.2 g, 52.5 mmol) in DMF (30 mL) wasadded sodium hydride (60% dispersion in mineral oil, 3.0 g, 75.0 mmol)at 0° C. After stirring at 0° C. for 20 min., ethyl iodide (5 mL, 62.5mmol) was added dropwise at 0° C. The mixture was stirred at rt for 1 h,and then partitioned between ethyl acetate and water. The aqueous layerwas extracted with ethyl acetate (3×). The combined organic phases werewashed with brine, and dried over anhydrous magnesium sulfate. TLCindicated that a 2:1 mixture of two isomers was formed. The mixture waspurified by flash chromatography (hexanes:ethyl acetate=4:1, then 1:1)to give 2.34 g of the title compound as a viscous oil (slow movingisomer).

[0907] Step B: 2-Ethyl-3-bromoindazole

[0908] To a solution of 2-ethylindazole (2.32 g, 15.87 mmol) in ethanol(20 mL) was added bromine (2.54 g, 15.87 mmol) in ethanol (1 mL)/water(1 mL) at 0° C. After stirring at 0° C. for 10 min. and at rt for 1 h,the reaction was quenched with aq. sodium bicarbonate. The mixture waspartitioned between ethyl acetate and aq. sodium bicarbonate. Theaqueous layer was extracted with ethyl acetate (3×). The combinedorganic phase was washed with brine, and dried over anhydrous magnesiumsulfate. Purification by flash chromatography (hexanes: ethyl acetate=1:1, then 100% ethyl acetate) gave 2.34 g of the title compound as aviscous oil.

[0909] Step C:1-(t-Butoxycarbonyl)-4-hydroxy-4-(2-ethyl-indazol-3-yl)piperidine

[0910] To a solution of 2-ethyl-3-bromoindazole (3.4 g, 15.18 mmol) inTHF (30 mL) was added t-BuLi (1.7 M in pentane, 10.72 mL, 18.22 mmol)dropwise at −78° C. After stirring at −78° C. for 20 min., was addedtert-butyl 4-oxo-1-piperidinecarboxylate (3.03 g, 15.18 mmol) in THF (10mL) dropwise at −78° C. The mixture was stirred at −78° C. for 10 min.and at rt for 18 h. After the reaction was quenched with aq. NH₄Cl, themixture was partitioned between ethyl acetate and water. The aqueouslayer was extracted with ethyl acetate (3×). The combined organic phaseswere washed with brine, and dried over anhydrous magnesium sulfate.Concentration followed by purification by flash chromatography (hexanesethyl acetate=4:1, then 1:1) to give 1.18 g of the title compound as afoamy solid.

[0911] Step D:1-(t-Butoxycarbonyl)-4-(2-ethyl-indazol-3-yl)-[1,2,3,6]tetrahydropyridine

[0912] To a solution of1-(t-butoxycarbonyl)-4-hydroxy-4-(2-ethyl-indazol-3-yl)piperidine (651mg, 1.89 mmol) in toluene (5 mL) was added(methoxycarbonylsulfamoyl)-triethylammonium hydroxide inner salt (540mg, 2.27 mmol). After heating up to ˜70° C. for 10 min., was addedadditional 5 mL of toluene. The mixture was stirred at 70° C. foradditional 2 h. The mixture was partitioned between ethyl acetate andaq. sodium bicarbonate. Aqueous layer was extracted with ethyl acetate(3×). The combined organic phases were washed with brine, and dried overanhydrous magnesium sulfate. Concentration followed by purification byflash chromatography (hexanes:ethyl acetate=4:1, then 1:1) gave 514 mgof the title compound as a viscous oil.

[0913] Step E:1-(t-Butoxycarbonyl)-4-(2-ethyl-[5,6,7,8]tetrahydroindazol-3-yl)piperidine

[0914] A solution of1-(t-butoxycarbonyl)-4-(2-ethyl-indazol-3-yl)-[1,2,3,6]tetrahydropyridine(500 mg, 1.53 mmol) in methanol (5 mL) was hydrogenated using Pd(OH)2(100 mg) under atmospheric H₂ for 4.5 h. After the addition of Platinum(IV) oxide (100 mg) hydrogenation was continued for additional 4 h. Themixture was filtered through celite and concentrated to give the titlecompound (461 mg) as a viscous oil. ESI-MS 333 (M+1); HPLC A: 2.45 min.

[0915] Step F: 1-(t-Butoxycarbonyl)-4-(2-ethylindazol-3-yl)piperidine

[0916] To a solution of1-(t-butoxycarbonyl)-4-(2-ethyl-[5,6,7,8]tetrahydroindazol-3-yl)piperidine(80 mg, 0.24 mmol) in toluene (3 mL) was added DDQ (115 mg, 0.51 mmol)at rt. After refluxing for 4 h, the mixture was partitioned betweenethyl acetate and water. The aqueous layer was extracted with ethylacetate (3×). The combined organic phases were washed with brine, anddried over anhydrous magnesium sulfate. Concentration gave 25 mg of thetitle compound as a viscous oil.

[0917] ESI-MS 274 (M+1-t-Bu); HPLC A: 3.09 min.

[0918] Step G: 4-(2-Ethylindazol-3-yl)piperidine, TFA Salt

[0919] Using essentially the same method as Procedure 27, Step B, thetitle compound was obtained as the TFA salt

Procedure 45

[0920] 4-(1,3-Diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine Di-HCl Salt

[0921] Step A:1-(t-Butoxycarbonyl)-4-(N-methyl-N-methoxycarboxamido)piperidine

[0922] A solution of 1-(t-butoxycarbonyl)isonipecotic acid (13.74 g,0.06 mol), TEA (14.7 mL, 0.105 mol), 4-DMAP (1.83 g, 0.015 mol),N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide×HCl (11.50 g, 0.06 mol)and O,N-dimethylhydroxylamine×HCl (6.27 g, 0.09 mol) in methylenechloride (250 mL) was stirred at rt for 60 h. The mixture waspartitioned between 1 L of ether and 500 mL of water and the layers wereseparated. The organic layer was washed with 500 mL of 1.0 N HCl, 500 mLof 1.0 N NaOH, 500 mL of sat'd sodium chloride, dried over magnesiumsulfate and concentrated to afford 14.34 g (88%) of the title compound:

[0923]¹H NMR (500 MHz) δ 1.46 (s, 9H), 1.65-1.80 (4H), 2.76-2.86 (3H),3.19 (s, 3H), 3.71 (s, 3H), 4.15 (2H).

[0924] Step B: 1-(t-Butoxycarbonyl)-4-formylpiperidine

[0925] A solution of1-(t-butoxycarbonyl)-4-(N-methyl-N-methoxycarboxamido)piperidine (4.80g, 17.6 mmol) (from Step A) in methylene chloride (100 mL) at −78° C.was treated with 1.0 M DIBALH solution in methylene chloride (25 mL) andstirred cold for 30 min. The reaction was quenched with 1.0 N HCl (250mL) and warmed to rt. The quenched mixture was extracted with 300 mL ofether; the extract was washed with 150 mL of 1.0 N NaOH, 150 mL of sat'dsodium chloride, dried over magnesium sulfate and concentrated. Flashchromatography on 125 g of silica gel using 1:1 v/v hexanes/ether as theeluant afforded 3.60 g (95%) of the title compound:

[0926]¹H NMR (500 MHz) δ 1.46-(s, 9H), 1.52-1.59 (m, 2H), 1.85-1.91 (m,2H), 2.38-2.43 (m, 1H), 2.93 (app t, J=11.0, 2H), 3.95-4.05 (m, 2H),9.66 (s, 1H).

[0927] Step C:1-(t-Butoxycarbonyl)-4-(1-(RS)-hydroxy-2-(RS)-methyl-3-oxopent-1-yl)piperidine

[0928] A solution of diisopropylamine (0.63 mL, 4.5 mmol) in THF (16 mL)at 0° C. was treated with 1.6 M n-butyllithium in sol'n in hexanes (2.8mL). The resulting solution was stirred at 0° C. for 10 min, then cooledto −78° C. 3-Pentanone (0.41 mL, 4.1 mmol) was added and the resultingmixture was stirred cold for 1 h. A solution of1-(t-butoxycarbonyl)4-formylpiperidine (435 mg, 2.05 mmol) (from Step B)in THF (3 mL) was then added. After 15 min, the reaction was quenchedwith sat'd ammonium chloride (25 mL) and extracted with ether (100 mL).The extract was dried over magnesium sulfate and concentrated. MPLC(Biotage) on a 40S silica cartridge using 4:1 v/v, then 3:2 v/vhexanes/ethyl acetate as the eluent afforded 517 mg (85%) of the titlecompound.

[0929] Step D:1-(t-Butoxycarbonyl)-4-(1,3-dioxo-2-(RS)-methylpent-1-yl)piperidine

[0930] A solution of oxalyl chloride (0.34 mL, 3.9 mmol) in methylenechloride (12 mL) at −78° C. was treated with DMSO (0.43 mL, 6.0 mmol)and the resulting mixture was stirred cold for 10 min. A solution of1-(t-butoxycarbonyl)-4-(1-(RS)-hydroxy-2-(RS)-methyl-3-oxopent-1-yl)piperidine(514 mg, 1.7 mmol) (from Step C) was added and the resulting solutionwas stirred cold for 1 h. N,N-Diisopropylethylamine (2.4 mL, 13.7 mmol)was added and the resulting mixture was warmed to 0° C. The reaction wasquenched with 1.0 N HCl (25 mL) and extracted with ether (100 mL). Theextract was dried over magnesium sulfate and concentrated. MPLC(Biotage) on a 40S silica cartridge using 2:1 v/v hexanes/ethyl acetateas the eluent afforded 435 mg (85%) of the title compound.

[0931] Step E:1-(t-Butoxycarbonyl)-4-(1,3-diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine

[0932] A solution of1-(t-butoxycarbonyl)-4-(1,3-dioxo-2-(RS)-methylpent-1-yl)piperidine (435mg, 1.5 mmol) (from Step D) in 2:1 v/v acetonitrile/water (12 mL) wastreated with ethylhydrazine (34% sol'n in water, 0.28 mL, 1.6 mmol) andthe resulting mixture was stirred at rt for 20 h. The reaction mixturewas partitioned between 75 mL of ether and 25 mL of sat'd sodiumchloride and the layers were separated. The organic layer was dried overmagnesium sulfate and concentrated. MPLC (Biotage) on a 40S silicacartridge using 4:1 v/v, then 1:1 v/v hexanes/ethyl acetate as theeluent afforded 348 mg (74%) of the title compound:

[0933]¹H NMR (500 MHz) δ 1.21 (t, J=7.5, 3H), 1.36 (t, J=7.5, 3H), 1.49(s, 9H), 1.68-1.72 (m, 2H), 1.86-1.91 (m, 2H), 2.54 (q, J=1.5, 2H),2.72-2.79 (3H), 4.08 (q, J=7.5, 2H), 4.20-4.30 (m, 2H).

[0934] Step F: 4-(1,3-Diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidineDi-HCl Salt

[0935] A solution of1-(t-butoxycarbonyl)-4-(1,3-diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine(348 mg) (from Step E) in 2.5 N HCl in methanol was stirred at rt for 16h. The solution was concentrated and the resulting solid was suspendedin ethyl acetate, filtered and dried to afford 293 mg (92%) of the titlecompound.

Procedure 46

[0936] Using essentially the same methods as described in Procedure 45and substituting the appropriate starting material and/or hydrazinereagent, a variety of other4-(1,3,4-trialkyl)-(1H)-pyrazol-5-yl)piperidines can be prepared,usually as the di-hydrochloride salts, and utilized in the followingExamples as required.

Procedure 47

[0937] Using essentially the same methods as described in Procedures 1and 2 and substituting the appropriate starting material and/orhydrazine reagent, the following representative 4-(3-(substituted)-1-(Hor alkyl)-(1H)-pyrazol-5-yl)piperidines can be prepared, usually as thedi-hydrochloride salts, and utilized in the following Examples asrequired.

[0938] 4-(3-(Benzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine

[0939] 4-(3-(Benzyl)-1-(n-propyl)-(1H)-pyrazol-5-yl)piperidine

[0940] 4-(3-(Benzyl)-1-(isopropyl)-(1H)-pyrazol-5-yl)piperidine

[0941] 4-(3-(2-Pluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0942] 4-(3-(3-Fluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0943] 4-(3-(4-Fluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0944] 4-(3-(4-Fluorobenzyl)-(1H)-pyrazol-5-yl)piperidine

[0945] 4-(3-(4-Fluorobenzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine

[0946] 4-(3-(4-Fluorobenzyl)-1-(n-propyl)-(1H)-pyrazol-5-yl)piperidine

[0947] 4-(3-(3,4-Difluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0948] 4-(3-(3,4-Difluorobenzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine

[0949] 4-(3-(3,4-Difluorobenzyl)-(1H)-pyrazol-5-yl)piperidine

[0950] 4-(3-(3,5-Difluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0951] 4-(3-(2,4-Difluorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0952] 4-(3-(3-Chlorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0953] 4-(3-(4-Chlorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0954] 4-(3-(3,4-Dichlorobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0955] 4-(3-(3-Cyanobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0956] 4-(3-(4-Cyanobenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0957]4-(3-(3-Methylsulfonylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0958]4-(3-(4-Methylsulfonylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0959] 4-(3-(3-Methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0960] 4-(3-(4-Methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0961] 4-(3-(4-Methoxybenzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine

[0962] 4-(3-(4-Methoxybenzyl)-(1H)-pyrazol-5-yl)piperidine

[0963] 4-(3-(3-Ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0964] 4-(3-(4-Ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0965] 4-(3-(4-Ethoxybenzyl)-(1H)-pyrazol-5-yl)piperidine

[0966] 4-(3-(3-Isopropoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0967] 4-(3-(4-Isopropoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0968]4-(3-(4-Cyclopropoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0969] 4-(3-(4-Butoxybenzyl)-1-(ethyl)-(H)-pyrazol-5-yl)piperidine

[0970] 4-(3-(4-t-Butoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0971] 4-(3-(4-Cyclobutoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0972]4-(3-(4-Difluoromethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0973]4-(3-(4-Trifluoromethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0974]4-(3-(4-Trifluoroethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0975] 4-(3-(3,4-Methylenedioxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0976] 4-(3-(3,4-Dimethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0977] 4-(3-(3,4-Diethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0978]4-(3-(3-Fluoro-4-methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0979]4-(3-(4-Fluoro-3-methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0980]4-(3-(3-Fluoro-4-ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0981]4-(3-(4-Fluoro-3-ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0982]4-(3-(3-Cyano-3-methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0983]4-(3-(4-Cyano-3-methoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0984]4-(3-(3-Cyano-4-ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0985]4-(3-(4-Cyano-3-ethoxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0986] 4-(3-(Benzofuran-6-yl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0987] 4-(3-(Benzofuran-5-yl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0988]4-(3-(2,3-Dihydrobenzofuran-6-yl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0989] 4-(3-(4-Benzyloxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0990] 4-(3-(4-Hydroxybenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0991] 4-(3-(3-Methylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0992] 4-(3-(4-Methylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0993] 4-(3-(3-Ethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0994] 4-(3-(4-Ethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0995] 4-(3-(4-Ethylbenzyl)-1-(methyl)-(1H)-pyrazol-5-yl)piperidine

[0996] 4-(3-(4-Ethylbenzyl)-(1H)-pyrazol-5-yl)piperidine

[0997] 4-(3-(4-Isopropylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0998] 4-(3-(4-t-Butylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[0999]4-(3-(4-Trifluoromethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1000] 4-(3-(3-Phenylbenzyl)-1-(ethyl)-(H)-pyrazol-5-yl)piperidine

[1001] 4-(3-(4-Phenylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1002] 4-(3-(4-Naphthyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1003] 4-(3-(2-Naphthyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1004] 4-(3-(4-Acetylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1005]4-(3-(4-(1-Methyl-1-hydroxyethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1006]4-(3-(3-Trifluoromethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1007]4-(3-(4-Trifluoromethylbenzyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1008] 4-(3-(Pyridin-3-yl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1009] 4-(3-(Pyridin-3-yl)-(1H)-pyrazol-5-yl) piperidine

[1010] 4-(3-(Cyclohexylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1011]4-(3-(4-Methylcyclohexylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1012] 4-(3-(Cycloheptylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1013] 4-(3-(Pyran-4-ylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine

[1014]4-(3-(Thiopyran-4-ylmethyl)-1-(ethyl)-(1H)-pyrazol-5-yl)piperidine,S,S-dioxide

Procedure 48

[1015] Using essentially the same methods as described in Procedures22-26 and substituting the appropriate starting material and/or reagent,the following representative 4-(2-(substituted)-4-(H oralkyl)thiazol-5-yl)piperidines can be prepared, usually as thedi-hydrochloride salts, and utilized in the following Examples asrequired.

[1016] 4-(2-(Benzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1017] 4-(2-(Benzyl)-4-(methyl)thiazol-5-yl)piperidine

[1018] 4-(2-(Benzyl)thiazol-5-yl)piperidine

[1019] 4-(2-(2-Fluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1020] 4-(2-(2-Fluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1021] 4-(2-(2-Fluorobenzyl)thiazol-5-yl)piperidine

[1022] 4-(2-(3-Fluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1023] 4-(2-(3-Fluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1024] 4-(2-(3-Fluorobenzyl)thiazol-5-yl)piperidine

[1025] 4-(2-(4-Fluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1026] 4-(2-(4-Fluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1027] 4-(2-(4-Fluorobenzyl)thiazol-5-yl)piperidine

[1028] 4-(2-(2-Chlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1029] 4-(2-(2-Chlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1030] 4-(2-(2-Chlorobenzyl)thiazol-5-yl)piperidine

[1031] 4-(2-(3-Chlorobenzyl)-4-(ethyl)thiazo-5-y)piperidine

[1032] 4-(2-(3-Chlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1033] 4-(2-(3-Chlorobenzyl)thiazol-5-yl)piperidine

[1034] 4-(2-(4-Chlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1035] 4-(2-(4-Chlorobenzyl)-4-(methyl)thiazol-5-yl)pipeidine

[1036] 4-(2-(4-Chlorobenzyl)thiazol-5-yl)piperidine

[1037] 4-(2-(3-Cyanobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1038] 4-(2-(3-Cyanobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1039] 4-(2-(3-Cyanobenzyl)thiazol-5-yl)piperidine

[1040] 4-(2-(4-Cyanobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1041] 4-(2-(4-Cyanobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1042] 4-(2-(4-Cyanobenzyl)thiazol-5-yl)piperidine

[1043] 4-(2-(3,4-Difluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1044] 4-(2-(3,4-Difluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1045] 4-(2-(3-4-Difluorobenzyl)thiazol-5-yl)piperidine

[1046] 4-(2-(3,5-Difluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1047] 4-(2-(3,5-Difluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1048] 4-(2-(3,5-Difluorobenzyl)thiazol-5-yl)piperidine

[1049] 4-(2-(2,4-Difluorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1050] 4-(2-(2,4-Difluorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1051] 4-(2-(2,4-Difluorobenzyl)thiazol-5-yl)piperidine

[1052] 4-(2-(3,4-Dichlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1053] 4-(2-(3,4-Dichlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1054] 4-(2-(3,4-Dichlorobenzyl)thiazol-5-yl)piperidine

[1055] 4-(2-(3,5-Dichlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1056] 4-(2-(3,5-Dichlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1057] 4-(2-(3,5-Dichlorobenzyl)thiazol-5-yl)piperidine

[1058] 4-(2-(2,4-Dichlorobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1059] 4-(2-(2,4-Dichlorobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1060] 4-(2-(2,4-Dichlorobenzyl)thiazol-5-yl)piperidine

[1061] 4-(2-(3-Methylbenzyl)4-(ethyl)thiazol-5-yl)piperidine

[1062] 4-(2-(3-Methylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1063] 4-(2-(3-Methylbenzyl)thiazol-5-yl)piperidine

[1064] 4-(2-(4-Methylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1065] 4-(2-(4-Methylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1066] 4-(2-(4-Methylbenzyl)thiazol-5-yl) piperidine

[1067] 4-(2-(3-Ethylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1068] 4-(2-(3-Ethylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1069] 4-(2-(3-Ethylbenzyl)thiazol-5-yl) piperidine

[1070] 4-(2-(4-Ethylbenzyl)4-(ethyl)thiazol-5-yl)piperidine

[1071] 4-(2-(4-Ethylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1072] 4-(2-(4-Ethylbenzyl) thiazol-5-yl) piperidine

[1073] 4-(2-(4-Isopropylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1074] 4-(2-(4-Isopropylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1075] 4-(2-(4-Isopropylbenzyl )thiazol-5-yl)piperidine

[1076] 4-(2-(4-t-Butylbenzyl)4-(ethyl)thiazol-5-yl)piperidine

[1077] 4-(2-(4-t-Butylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1078] 4-(2-(4-t-Butylbenzyl)thiazol-5-yl)piperidine

[1079] 4-(2-(3-Trifluoromethylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1080] 4-(2-(3-Trifluoromethylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1081] 4-(2-(3-Trifluoromethylbenzyl)thiazol-5-yl)piperidine

[1082] 4-(2-(4-Trifluoromethylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1083] 4-(2-(4-Trifluoromethylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1084] 4-(2-(4-Trifluoromethylbenzyl)thiazol-5-yl) piperidine

[1085] 4-(2-(3-Methoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1086] 4-(2-(3-Methoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1087] 4-(2-(3-Methoxybenzyl)thiazol-5-yl)piperidine

[1088] 4-(2-(4-Methoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1089] 4-(2-(4-Methoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1090] 4-(2-(4-Methoxybenzyl)thiazol-5-yl)piperidine

[1091] 4-(2-(3-Ethoxybenzyl)4-(ethyl)thiazol-5-yl)piperidine

[1092] 4-(2-(3-Ethoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1093] 4-(2-(3-Ethoxybenzyl)thiazol-5-yl)piperidine

[1094] 4-(2-(4-Ethoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1095] 4-(2-(4-Ethoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1096] 4-(2-(4-Ethoxybenzyl)thiazol-5-yl)piperidine

[1097] 4-(2-(3-Trifluoromethoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1098] 4-(2-(3-Trifluoromethoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1099] 4-(2-(3-Trifluoromethoxybenzyl)thiazol-5-yl)piperidine

[1100] 4-(2-(4-Trifluoromethoxybenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1101] 4-(2-(4-Trifluoromethoxybenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1102] 4-(2-(4-Trifluoromethoxybenzyl)thiazol-5-yl)piperidine

[1103] 4-(2-(4-Methylsulfonylbenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1104] 4-(2-(4-Methylsulfonylbenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1105] 4-(2-(4-Methylsulfonylbenzyl)thiazol-5-yl)piperidine

[1106] 4-(2-(4-Nitrobenzyl)-4-(ethyl)thiazol-5-yl)piperidine

[1107] 4-(2-(4-Nitrobenzyl)-4-(methyl)thiazol-5-yl)piperidine

[1108] 4-(2-(4-Nitrobenzyl)thiazol-5-yl) piperidine

Procedure 49

[1109] 4-(3-Benzyl-1-ethyl-(1-pyrazol-5-yl)piperidine di-HCl salt

[1110] A 100 L round-bottomed-flask equipped with a mechanical stirrer,thermocouple and nitrogen inlet was charged with DMF (51 L),N,O-dimethylhydroxyamine hydrochloride (2.62 Kg, 26.55 mol), HOBT (1.2Kg, 8.85 mol), and N-Boc isonipecotic acid (4.10 Kg, 17.70 mol). Themixture warmed to 18° C. as the diisopropylethylamine (4.60 Kg, 6.2 L,35.41 mol) was added over 15 min. The EDC.HCl (5.09 Kg, 26.55 mol) wasadded in three portions over 3 h maintaining an internal temperature of18° C. with gentle cooling. The reaction mixture was held at 18° C. for12 h. HPLC analysis shows no remaining 1. The reaction mixture waspumped into an extractor containing 74 L of water at 5° C. The resultingsolution (39.3 g/L of 2) was extracted with ethyl acetate (4×37 L).

[1111] The organic phases were combined and washed with 1 N HCl (2×7 L),water (5 L), then brine (10 L then 5 L). The final organic phase was125.4 Kg (d =0.878) with a concentration of 2 at 36.9 g/L (5.27 Kg).

[1112] The ethyl acetate solution of(1-(t-butoxycarbonyl)piperidin-4-yl)-N-methyl-N-methoxycarboxamide fromStep A (4.44 Kg, 16.29 mol) was dried over anhydrous sodium sulfate (1.6Kg). The drying agent was removed by filtration then the solvent wasremoved in vacuo to provide a clear light yellow oil that was held for16 h under high vacuum to provide a crystalline solid. The solid wasdissolved in THF (55 L) then cooled to −20° C. Methyl magnesium chloride(3.12 M in THF, 12.0 L, 37.4 mol) was added over 1.75 h keeping theinternal temperature below 0° C. The resulting gray suspension was agedat 0° C. for 2 h then 25° C. for 3 h. An aliquot was drawn and worked upwith ethyl acetate, acetic acid and water. The batch was cooled to 9°C., then pumped over 15 min into an extractor charged with a solution of41 L of water and 4.9 L of acetic acid at 5° C. Ethyl acetate (52 L) wascharged to the extractor, the phases were mixed then the lower aqueousphase (44.3 Kg) was cut away. The organic phase was washed with sat'daq. sodium bicarbonate (2×), 7% aq. sodium chloride (2×) and sat'd aq.sodium chloride. The organic phase (116.2 L, 30.3 g/L of 3) contained3.52 Kg of the title compound 3 (87.5% yield from 1). The organic phasewas dried over anhydrous sodium sulfate (1.5 Kg). The drying agent wasremoved by filtration, then the solution was batch concentrated to anoil. The compound was diluted with THF and the batch was flushed with 20L of THF. The residual oil was diluted with THF (5 L).

[1113] A 72 L round-bottomed-flask equipped with a mechanical stirrer,nitrogen inlet, thermocouple and 5 L dropping funnel was placed in atemperature control bath. Under a nitrogen sweep, the flask was chargedwith the NaH (60% in mineral oil, 1.55 Kg, 38.75 mol) and THF (20 L).The batch warmed from 17° C. to 22° C. as methanol (0.10 Kg, 130 mL,3.09 mol) was added over 45 min (hydrogen evolution!!). The solution of1-(t-butoxycarbonyl)-4-acetylpiperidine from Step B (3.52 Kg, 15.49 mol)was added over 1 h. To the resulting suspension was added a solution ofthe methyl phenylacetate 2.46 Kg, 17.04 mol) and THF (5 L) over 8 hmaintaining a reaction temperature of about 25° C. by cooling as needed.The mixture was aged at 23° C. for 15 h.

[1114] The batch was cooled to 17° C. then pumped into a 100 L extractorcontaining a solution of concentrated HCl (3.3 L) and water (16 L) at−6° C. (caution, hydrogen evolution!!). The mixture was stirred, allowedto partition then the pH of the aqueous phase was checked (pH=1 to 2).The layers were partitioned and the organic phase was washed with asolution of saturated aqueous sodium bicarbonate (5 L) and brine (1 L)then brine (4 L). MTBE (7.7 L) was added to the extractor along with theacidic first aqueous phase. The mixture was shaken to mix well, allowedto partition then the aqueous was cut away. The sodium bicarbonate phasewas added, mixed, allowed to partition then the aqueous was cut away.The brine phase was added to the extractor, the mixture mixed, allowedto partition then the aqueous phase was cut away. The MTBE and THBphases were combined then concentrated to an oil. To the oil was addedsilica gel 60 (7 Kg) and 5% ethyl acetate/heptanes (10 L) with stirringto provide a slurry. The slurry was poured onto a column containingsilica gel 60 (23 Kg) wet with 5% ethyl acetate/heptanes. The column waseluted with 5% etyl acetate/heptanes (200 L) then 20% ethylacetate/heptanes (200 L) at the rate of 2.2 L/min to obtain the product4. The rich cut was batch concentrated to provide a slightly yellowslurry that was taken up in DMF (15 L) to provide a clear solution. Thebatch concentration was continued to remove all residual heptanes andethyl acetate. To the batch at 18° C. was slowly added water (3.5 L)until the mixture became turbid. The batch was seeded and additionalwater was added to a total of 8.0 L (final solvent mixture was 35% waterand 65% DMF). The batch was cooled to 1 ° C. The solids were collectedon a frit, washed with 5 L of water then dried under a stream ofnitrogen to provide 4 (3.57 Kg, 66.7% from 3, 57.8% from 1).

[1115] A 100 L cylindrical flask with a bottom valve was equipped with amechanical stirrer, internal heating coil, 5 L dropping funnel, andthermocouple was charged with the acetonitrile (39 L) and1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione 4 (3.00Kg, 8.68 mol). To the resulting clear light yellow solution was addedwater (18.6 l). The mixture was warmed to 19° C. and the mixture becameclear. An ethyl hydrazine solution (35% in water, 1.66 Kg, 1.71 L, 9.55mol) was added via a dropping funnel over 100 min. The batch temperatureafter the addition was 20° C. The reaction solution was aged for 1 h at20° C. then checked for completion by HPLC. If any 4 remained,additional ethyl hydrazine was added to complete the reaction. At theend of reaction the ratio of products 5:6:7 is 83.6:14.3:2.1 withcomplete consumption of 4.

[1116] The dropping funnel was removed and a Dean Stark trap was fittedto the flask. To the reaction mixture was added heptanes (5 L) and theacetonitrile was removed by azeotropic distillation at 64° C. During thedistillation, the initial reaction volume was maintaining by periodicaddition of heptanes. When the internal temperature reached 72° C., thebatch was cooled to 60° C. and the heavy aqueous phase was cut away. Thedistillation was resumed until the internal temperature reached 95° C.and no water droplets were observed in the distillate. The batch wascooled to 50° C., seeded then cooled to 5° C. over 16 h. The resultingsolids were collected on a frit, rinsed with heptanes (10 L at 5° C.),then dried under dry nitrogen to provide 2.58 Kg (80.3% yield) of acrystalline solid that was a 98.67:0.49:0.84 mixture of 5:6:7.

[1117] Step E: 4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidine di-HClSalt

[1118]1-(t-Butoxycarbonyl)4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-ylpiperidine 5from Step D (18.5 g, 50 mmol) was added to a solution of HCl (530 mmol)in methanol (300 mL) prepared by the slow addition of acetyl chloride(38 mL, 530 mmol) and aged for 90 min. The reaction was stirred at rtfor 16 h and then evaporated to dryness to afford 17.1 g (100%) of thetitle compound as a hygroscopic white solid.

EXAMPLE 1

[1119]N-(1-(SR)-3-(SR)-((4-(3-(Phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-1-leucineDi-Hydrochloride Salt andN-(1-(SR)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-D-leucineDi-Hydrochloride Salt

[1120] Step A: Methyl (+−)-trans-4-methylene-2-phenylcyclopentanoate

[1121] A mixture of methyl trans-cinnamate (5.0 g, 31 mmol),tetrakis(triphenylphosphine) palladium(0) (2.6 g, 2.3 mmol),1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) inTHF (60 mL) under argon was heated to reflux for 4 h. An additionalaliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g) wasadded and the reaction was continued for another 16 h. The volatileswere then removed in vacuo and the residue was purified by FC (10% ethylacetate in hexanes) to afford the title compound (6.2 g).

[1122]¹H NMR (CDCl₃) δ: 2.52 (m, 1H), 2.68 (m, 1H), 2.75-2.9 (m, 2H),2.95 (ddd, 1H), 3.45 (ddd, 1H), 3.57 (s, 3H), 4.92 (m, 2H), 7.15-7.3 (m,5H).

[1123] Step B:(+−)-trans-1-Hydroxymethyl-4-methylene-2-phenylcyclopentane

[1124] To a solution of methyl(+−)-trans4-methylene-2-phenylcyclopentanoate (26.0 g, 128 mmol)prepared as in Step A in THF (600 mL) under nitrogen and cooled to −10°C. was added dropwise over 15 min 1M lithium aluminum hydride (LAH) inTHF (193 mL). After 1 h, the bath was removed and the reaction wasstirred at rt for 16 h. The reaction was cooled in an ice/methanol bathand the excess LAH was quenched by dropwise addition of acetone. Thereaction was then poured into dilute aq. HCl. The mixture was extractedtwice with ether and the organic layers were washed with brine, driedover sodium sulfate, combined and concentrated. The residue was purifiedby FC (20-30% ethyl acetate in hexanes) to afford the title product(23.8 g).

[1125] Step C: (+−)-trans-1-Hydroxymethyl-4-oxo-2-phenylcyclopentane

[1126] Into a solution of(+−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step B(22.7 g, 121 mmol) in methanol (300 mL) cooled in a dry ice/acetone bathwas bubbled ozone until the blue color persisted. The excess ozone wasremoved with a stream of nitrogen and then dimethylsulfide (25 mL) wasadded. After 30 min, the bath was removed and the reaction was allowedto warrn to rt over 16 h. The volatiles were removed in vacuo and theresidue was purified by FC (15-30% ethyl acetate in hexanes) to give thetitle compound (22.1 g).

[1127]¹H NMR (CDCl₃) δ: 2.2-2.5 (m, 4H), 2.71 (dd, 1H), 3.28 (m, 1H),3.55 (dABq, 2H), 7.23 (m, 3H), 7.34 (m, 2H).

[1128] Step D:1-(SR)-Benzylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane and1-(RS)-benzylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane

[1129] To a solution of(+−)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane from Step C (9.8g, 52 mmol) in 1,2-dichloroethane (200 mL) was added benzylamine (11.3mL, 103 mmol) and acetic acid (6.2 mL, 103 mmol). After 10 min, sodiumtriacetoxyborohydride (33 g, 155 mmol) was added in portions and thereaction was stirred at rt for 3 h. The reaction was quenched intodilute aq. sodium carbonate and the mixture was extracted twice withethyl acetate. The organic layers were washed with brine, dried oversodium sulfate, combined and concentrated. The residue was purified byFC (1-5% methanol in ether) to obtain the title products (13.1 g) as amixture of C-1 isomers.

[1130] Step E:1-(SR)-Benzyloxycarbonylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) Isomer) and1-(RS)-benzyloxycarbonylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane(Lower R_(f) Isomer)

[1131] To a solution of1-(SR)-benzylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane and1-(RS)-benzylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane (13 g,46 mmol) from Step D was added 20% palladium hydroxide (2.5 g, 50% by wtwater), ammonium formate (60 g, 930 mmol) and an additional 200 mL ofmethanol. The reaction was heated at 60° C. for 6 h. The reaction wasfiltered and concentrated. The residue was taken up in water andextracted twice with methylene chloride to remove any remainingbenzylamine intermediate. The aqueous layer was made basic with 2Nsodium hydroxide and extracted twice with methylene chloride. Theorganic layers were washed with brine, dried over sodium sulfate,combined and concentrated to afford 8.1 g of crude amino-alcohol.

[1132] The above product (8.1 g, 42 mmol) was taken up in methylenechloride (200 mL), cooled in an ice bath and DIPEA (22 mL, 126 mmol) andbenzyl chloroformate (6.33 mL, 44 mmol) were added. After 2.5 h at rt,the reaction was poured into dilute aq. HCl and extracted twice withmethylene chloride. The organic layers were washed with brine, driedover sodium sulfate, combined and concentrated. The residue was purifiedby Prep LC (30-75% ethyl acetate in hexanes) to afford the titlecompounds (4.0 g higher, 6.6 g lower).

[1133] Step F:1-(SR)-Benzyloxycarbonylamino-3-(SR)-formyl-4-(SR)-phenylcyclopentane(Higher R_(f) Isomer) and1-(SS)-benzyloxycarbonylamino-3-(SR)-formyl-4-(SR)-phenylcyclopentane(Lower R_(f) Isomer)

[1134] To a solution of oxalyl chloride (0.350 mL, 3.85 mmol) inmethylene chloride (10 mL) at −70° C. was added dropwise DMSO (0.550 mL,7.65 mmol). After 15 min, a solution of1-(SR)-benzyloxycarbonylamino-3-(SR)-hydroxymethyl4-(SR)-phenylcyclopentane(Higher R_(f) isomer from Step E) (500 mg, 1.53 mmol) in methylenechloride (10 mL) was added. The reaction was stirred at −70° C. for 1 hand then DIPEA (2.7 mL, 15 mmol) in methylene chloride (5 mL) was addeddropwise over 5 min. After a further 10 min, the mixture was allowed towarm to rt for 1 h and then diluted with methylene chloride and pouredinto dilute aq. HCl. The layers were separated. The aq. layer wasreextracted with a second portion of methylene chloride and the organiclayers were each washed with brine, dried over sodium sulfate, combinedand concentrated in vacuo. The residue was purified by FC (20-30% ethylacetate in hexanes) to give the title product (465 mg) as an oil.

[1135]¹H NMR (CDCl₃) δ: 1.9-2.0 (m, 1H, 2b-H), 2.05-2.15 (m, 2 H, both5-H's), 2.3-2.45 (m, 1H, 2a-H), 3.06 (q, 1 H, 3-H), 3.47 (q, 1H, 4-H),4.32 (br m, 1H, 1-H), 4.94 (br s, 1H, NH), 5.08 (s, 2 H, CH₂O), 7.1-7.4(m, 10H), 9.74 (s, 1 H, COH). The assignment of cis stereochemistrybetween C-1 and C-3 and trans between C-1 and C-4 were confirmed by 2-DNOESY NMR.

[1136] Using essentially the same procedure as above, material derivedfrom the lower isomer from Step E (500 mg, 1.5 mmol) was also convertedto the lower R_(f) title compound (457 mg).

[1137]¹H NMR (CDCl₃) δ: 1.71 (q, 1H, 5a-H), 1.8-1.95 (m, 1H, 2a-H), 2.48(p, 1H, 2b-H), 2.5-2.6 (m, 1H, 5b-H), 3.0-3.1 (m, 1H, 3-H), 3.3-3.4 (m,1H, 4-H), 4.0-4.2 (m, 1H, 1-H), 4.82 (br s, 1H, NH), 5.08 (s, 2H, OCH₂),7.2-7.4 (m, 10H), 9.63 (d, 1 H, COH). The assignment of transstereochemistry between C-1 and C-3 and cis between C-1 and C-4 wereconfirmed by 2-D NOESY NMR.

[1138] Step G:1-(SR)-(Benzyloxycarbonylamino)-3-(SR)-((4-(3-phenylprop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane(Higher R_(f) Isomer)

[1139] To a solution of1-((SR)-(benzyloxycarbonylamino)-3-(SR)-(carbonyl)-4-(SR)-phenylcyclopentane(from Step F, derived from Higher R_(f) isomer in Step E) (450 mg, 0.1.4mmol) in 1,2-dichloroethane (10 mL) was added4-(3-phenylprop-1-yl)piperidine (424 mg, 2.1 mmol) and acetic acid(0.125 mL, 2.1 mmol). After 15 min, sodium triacetoxyborohydride (890mg, 4.2 mmol) was added in portions over 30 min and the reaction wasstirred at rt for 16 h. The reaction was diluted with methylenechloride, quenched with aq. sodium carbonate and extracted 3 times withmethylene chloride. The organic layers were each washed with brine,dried over sodium sulfate, combined and concentrated in vacuo. Theresidue was purified by FC (30-40% ethyl acetate in hexanes) to give thetitle product (698 mg) as the free amine.

[1140] MS (NH₃/ESI): m/z 511 (M+1).

[1141] Step H:1-(SR)-(Amino)-3-(SR)-((4-(3-phenylprop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane(Higher R_(f) Isomer)

[1142] To a solution of1-(SR)-(benzyloxycarbonylamino)-3-(SR)-((4-(3-phenylprop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane(from Step G, derived from the Higher R_(f) isomer from Step E) (500 mg,1.0 mmol) in methanol (10 mL) was added 10% Pd/C (100 mg). The mixturewas hydrogenated on a Parr shaker at 40 psi for 2 h and was thenfiltered and concentrated to afford the crude title compound (350 mg) asan oil.

[1143] Step I:N-(1-(SR)-3-(SR)-((4-(3-(Phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-1-leucinedi-hydrochloride salt andN-(1-(SR)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-D-leucinedi-hydrochloride salt

[1144] To a solution of1-(SR)-(amino)-3-(SR)-((4-(3-phenylprop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane(from Step H, derived from the Higher R_(f) isomer from Step E) (25 mg,0.067 mmol), 4-methyl-2-oxovaleric acid (17 mg, 0.13 mmol) and aceticacid (0.008 mL, 0.13 mmol) in 1,2-dichloroethane (2 mL) was added sodiumtriacetoxyborohydride (42 mg, 0.20 mmol). The reaction was stirred at rtfor 24 h and was then quenched into dilute aq. sodium carbonate solutionand was extracted three times with ethyl acetate. The organic layerswere washed with brine, dried over sodium sulfate, combined andevaporated. The residue was purified by Prep TLC (5% methanol inmethylene chloride) to afford separation of the 2 title compounds. Thehydrochlorides were prepared by taking up in methylene chloride,addition of excess 1M HCl in ether, and evaporation to dryness.

[1145] Higher: MS (NH3/ESI): m/z 491 (M+1).

[1146] Lower: MS (NH₃/ESI): m/z 491 (M+1).

EXAMPLE 2

[1147]N-(1-(RS)-3-(SR)-((4-(3-(Phenyl)prop-1-yl)piperidin-1-yl)methyl)4-(SR)-phenylcyclopent-1-yl)-1-leucineDi-Hydrochloride Salt andN-(1-(RS)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-D-leucineDi-Hydrochloride Salt

[1148] Using essentially the same procedures as in Example 1, Steps G-I,but substituting the lower R_(f) product from Steps E and F, the 2 titlecompounds were obtained after Prep TLC separation.

[1149] Higher: MS (NH₃/ESI): m/z 491 (M+1).

[1150] Lower: MS (NH₃/ESI): n/z 491 (M+1).

EXAMPLE 3

[1151]N-(1-(SR)-3-(SR)-((4-(3-(Phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-1-norvalineDi-Hydrochloride Salt andN-(1-(SR)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-D-norvalineDi-Hydrochloride Salt

[1152] Using essentially the same procedure as in Example 1, Step I, butsubstituting 2-oxovaleric acid in Step I, the 2 title compounds wereobtained as a mixture after Prep TLC purification (no separation of thediastereomers was seen in this case).

[1153] MS (NH₃/ESI): m/z 477 (M+1).

EXAMPLE 4

[1154]N-(1-(RS)-3-(SR)-((4-(3-(Phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-1-norvalineDi-Hydrochloride Salt andN-(1-(RS)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-D-norvalineDi-Hydrochloride Salt

[1155] Using essentially the same procedures as in Example 1, Steps G-I,but substituting the lower R_(f) product from Steps E and F and2-oxovaleric acid in Step I the 2 title compounds were obtained as amixture after Prep TLC purification (no separation of the diastereomerswas seen in this case).

[1156] MS (NH3/ESI): m/z 477 (M+1).

EXAMPLE 5

[1157]N-(1-(RS)-3-(SR)-((4-(3-(Phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-1-phenylglycineDi-Hydrochloride Salt andN-(1-(RS)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-D-phenylglycineDi-Hydrochloride Salt

[1158] Using essentially the same procedures as in Example 1, Steps G-I,but substituting the lower R_(f) product from Steps E and F and2-oxophenylacetic acid in Step I the 2 title compounds were obtained asa mixture after Prep TLC purification (no separation of thediastereomers was seen in this case).

[1159] HPLC/MS (ESI): m/z 511 (M+1).

[1160] Examples 6-9 illustrate the chemistry described in Schemes X-Y ofthe general chemistry section and were used to determine the absolutestereochemistry at the C-1, 3 and 4 positions of the cyclopentylscaffold for the intermediates and final products. This was then appliedto the preparation and assignment of stereochemistry for the subsequentExamples in this patent.

EXAMPLE 6

[1161]N-(1-(S)-3-(R)-((4-(N-(4-Nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-leucine(Isomer 6A),N-(1-(S)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucine(Isomer 6B),N-(1-(R)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucine(Isomer 6C) andN-(1-(R)-3-(R)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-leucine(Isomer 6D) Di-TFA Salts

[1162] Step A: (+−)-trans-4-Methylene-2-phenylcyclopentanoic Acid

[1163] To a solution of methyl(+−)-trans-4-methylene-2-phenylcyclopentanoate prepared as in Example 1,Step A (28.4 g, 131 mmol) in methanol (400 mL) was added 5N sodiumhydroxide (131 mL, 656 mmol). The reaction was heated at 65° C. for 1 hthen cooled and concentrated. The residue was diluted with water,acidified with 2M hydrochloric acid and extracted twice with methylenechloride. The organic layers were each washed with brine, dried oversodium sulfate, combined and concentrated in vacuo to give the crudetitle acid (27.2 g) which was used directly in Step B.

[1164] Step B:(+−)-trans-1-Hydroxymethyl-4-methylene-2-phenylcyclopentane

[1165] To a solution of (+−)-trans-4-methylene-2-phenylcyclopentanoicacid (26 g, 129 mmol) from Step A in THF (600 mL) under nitrogen at −10°C. was added dropwise over 15 min 1M lithium aluminum hydride (LAH) inTHF (193 mL, 193 mmol). After 16 h at rt, the excess LAH was quenched bydropwise addition of acetone and the reaction was then poured intodilute aq. HCl. The mixture was extracted twice with ether and theorganic layers were washed with brine, dried over sodium sulfate,combined and concentrated. The residue was purified by FC (20% ethylacetate in hexanes) to afford the title product (23.8 g) as an oil.

[1166] Step C: (+−)-trans-1-Hydroxymethyl-4-oxo-2-phenylcyclopentane

[1167] Into a solution of(+−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step B(22.7 g, 121 mmol) in methanol (200 mL) cooled in a dry ice/acetone bathwas bubbled ozone until the blue color persisted. The excess ozone wasremoved with a stream of nitrogen and then dimethylsulfide (20 mL) wasadded. After 10 min, the bath was removed and the reaction was allowedto warm to rt over 16 h. The volatiles were removed iii vacuo and theresidue was purified by FC (15-30% ethyl acetate in hexanes) to give thetitle compound (22.1 g).

[1168] Step D: (+−)-trans-4-Oxo-2-phenylcyclopentanecarboxaldehyde

[1169] To a solution of oxalyl chloride (1.15 mL, 13.1 mmol) inmethylene chloride (30 mL) at −70° C. was added dropwise DMSO (1.87 mL,26.3 mmol). After 15 min, a solution of(+−)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane from -Step C (1.0g, 5.26 mmol) in methylene chloride (10 mL) was added. The reaction wasstirred at −70° C. for 1.5 h and then DIPEA (9.25 mL, 53 mmol) inmethylene chloride (10 mL) was added dropwise over 5 min. After afurther 10 min, the mixture was allowed to warm to rt for 1 h and thendiluted with methylene chloride and poured into dilute aq. HCl. Thelayers were separated. The aq. layer was reextracted with a secondportion of methylene chloride and the organic layers were each washedwith brine, dried over sodium sulfate, combined and concentrated invacuo. The residue was purified by FC (30% ethyl acetate in hexanes) togive the title product (0.9 g) after vacuum drying.

[1170] Step E:3-(SR)-((4-(N-(4-Nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentan-1-oneDi-Hydrochloride Salt

[1171] To a solution of(+−)-trans-4-oxo-2-phenylcyclopentanecarboxaldehyde from Step D (327 mg,1.74 mmol) in 1,2-dichloroethane (20 mL) was added4-(N-(4-nitrobenzyloxycarbonyl)(N-allyl)amino)piperidine hydrochloride(667 mg, 1.9 mmol) and DIPEA (0.36 mL, 2.1 mmol). After 5 min, sodiumtriacetoxyborohydride (740 mg, 3.5 mmol) was added and the reaction wasstirred at rt for 4 h. The reaction was diluted with methylene chloride,quenched with aq. sodium carbonate and extracted 3 times with methylenechloride. The organic layers were each washed with brine, dried oversodium sulfate, combined and concentrated in vacuo. The residue waspurified by FC eluting with a gradient of 35 to 75% ethyl acetate inhexanes to give the title product (365 mg) as the free amine. This wastaken up in ether and 1M hydrogen chloride in ether (0.5 mL) was addedto form the di-hydrochloride salt. The volatiles were removed in vacuoto give the title salt.

[1172] MS (NH₃/ESI): m/z 492 (M+1).

[1173] Step F:N-(1-(S)-3-(R)-((4-(N-(4-Nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-leucinet-butyl ester (Isomer A),N-(1-(S)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucinet-butyl ester (Isomer B),N-(1-(R)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)4-(S)-phenylcyclopent-1-yl)-1-leucine t-butyl Ester (Isomer C)andN-(1-(R)-3-(R)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-leucinet-butyl Ester (Isomer D)

[1174] To a solution of3-(SR)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)4-(SR)-phenylcyclopentan-1-one(52 mg, 0.10 mmol) from Step E, L-leucine t-butyl ester hydrochloride(65 mg, 0.29 mmol) and DIPEA (0.069 mL, 0.40 mmol) in 1,2-dichloroethane(2 mL) at rt was added sodium triacetoxyborohydride (41 mg, 0.20 mmol).The reaction was stirred at rt for 16 h and was then diluted withmethylene chloride, quenched with aq. sodium carbonate and extracted 3times with methylene chloride. The organic layers were each washed withbrine, dried over sodium sulfate, combined and concentrated in vacuo.The residue was purified by Prep TLC eluting first with 75% ethylacetate in hexanes to give partial separation of the four diastereomerictitle products. Prep TLC was repeated with 40% ethyl acetate in hexanesfor each band to give clean highest R_(f) product (Isomer A), a mixtureof the middle R_(f) products (Isomers B and C), and clean lowest R_(f)product (Isomer D) as the free amines.

[1175] (higher R_(f)): HPLC/MS (ESI): m/z 663 (M+1).

[1176] (middle R_(f)): HPLC/MS (ESI): m/z 663 (M+1) (2 isomers seen).

[1177] (lower R_(f)): HPLC/MS (ESI): m/z 663 (M+1).

[1178] Step G:N-(1-(S)-3-(R)-((4-(N-(4-Nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-leucine(Isomer 6A),N-(1-(S)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucine(Isomer 6B),N-(1-(R)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperdin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucine(Isomer 6C) andN-(1-(R)-3-(R)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-leucinc(Isomer 6D) di-TFA Salts

[1179] The 2 individual diastereomers and the mixed diastereomers fromStep F were each taken up in 1:1 methylene chloride:ether (2 mL) and 1Mhydrogen chloride in ether (1 mL) was added. After 3 days at rt thevolatiles were removed under nitrogen to give the title compounds aswhite solids. These were analyzed by HPLC (Advantage 4.6×150 mm C-18column, using a gradient of 10% A:90% B to 35% A:65% B over 30 min;A=0.5% TFA in water, B=0.5% TFA in acetonitrile) and purified by PrepHPLC (Combi Prep 20×50 mm C-18). Evaporation of the clean fractions todryness afforded the title compounds as their di-TFA salts.

[1180] Isomer A (from highest R_(f)): HPLC/MS (ESI): m/z 607 (M+1),R_(t)=25.5 min

[1181] Isomer B (from middle R_(f)): BPLC/MS (ESI): m/z 607 (M+1),R_(t)=25.2 min.

[1182] Isomer C (from middle R_(f)): HPLC/MS (ESI): m/z 607 (M+1),R_(t)=25.9 min.

[1183] Isomer D (from lowest R_(f)): BPLC/MS (ESI): m/z 607 (M+1),R_(t)=25.2 min.

EXAMPLE 7

[1184]N-(1-(R)-3-(S)-((4-(N-(4-Nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Isomer 7E),N-(1-(R)-3-(R)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-D-leucine(Isomer 7F),N-(1-(S)-3-(R)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-D-leucine(Isomer 7G) andN-(1-(S)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Isomer 7H) Di-TFA Salts

[1185] Using essentially the same procedures as in Example 6, Step F andG, but substituting D-leucine t-butyl ester hydrochloride in Step F, thefour title diastereomers were obtained which were enantiomeric to thoseof Example 6.

[1186] Isomer E (from highest R_(f)): HPLC/MS (ESI): m/z 607 (M+1),R_(t)=25.5 min

[1187] Isomer F (from middle R_(f)): HPLC/MS (ESI): m/z 607 (M+1),R_(t)=25.2 min.

[1188] Isomer G (from middle R_(f)): HPLC/MS (ESI): m/z 607 (M+1),R_(t)=25.9 min.

[1189] Isomer H (from lowest R_(f)): HPLC/MS (ESI): m/z 607 (M+1),R_(t)=25.2 min.

EXAMPLE 8

[1190] N-(1-(S)-3-(S)-((4-(N-(4-Nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-L-leucine(Isomer 6B) andN-(1-(S)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Isomer 7H) di-TFA Salts

[1191] Step A: (+−)-trans-4-Methylene-2-phenylcyclopentanoic Acid

[1192] To a solution of methyl(+−)-trans-4-methylene-2-phenylcyclopentanoate prepared as in Example 1,Step A (28.4 g, 131 mmol) in methanol (400 mL) was added 5N sodiumhydroxide (131 mL, 656 mmol). The reaction was heated at 65° C. for 1 hthen cooled and concentrated. The residue was diluted with water,acidified with 2M hydrochloric acid and extracted twice with methylenechloride. The organic layers were each washed with brine, dried oversodium sulfate, combined and concentrated in vacuo to give the crudetitle acid (27.2 g) which was used directly in Step B.

[1193] Step B: (+)-trans-4-Methylene-2-phenylcyclopentanoic acid,(S)-(−)-α-methylbenzylamine Salt and(−)-trans-4-methylene-2-phenylcyclopentanoic Acid,(R)-(+)-α-methylbenzylamine Salt

[1194] The crude (+−)-trans-4-methylene-2-phenylcyclopentanoic acid fromStep A (assumed 131 mmol) was taken up in 2-propanol (400 mL), warmed to80° C. and treated with (S)-(−)-a-methylbenzylamine (8.45 mL, 66 mmol).The mixture was stirred while allowed to cool to rt over 16 h and wasthen cooled to −10° C. for 1 h. The salt was filtered, washed with asmall amount of ether to remove 2-propanol and air dried to give 6.442 gof salt. This was recrystallized twice from 2-propanol to give the titlesalt (4.713 g), [α]_(D)=+56 (MeOH, c=0.20).

[1195] The combined mother liquors from above were concentrated and theresidue was taken up in water, acidified with 2M hydrochloric acid andextracted twice with methylene chloride. The organic layers were eachwashed with brine, dried over sodium sulfate, combined and concentratedin vacuo. The residue was taken up in 2-propanol (400 mL), warmed to 80°C. and treated with (R)-(+)-α-methylbenzylamine (9.1 mL, 70 mmol). Themixture was stirred while allowed to cool to rt over 16 h and was thencooled to −10° C. for 1 h. The salt was filtered, washed with a smallamount of ether to remove 2-propanol and air dried to give 8.22 g ofsalt. This was recrystallized from 2-propanol to give the title salt(6.31 g), [α]_(D)=−55 (MeOH, c=0.21).

[1196] Step C: (+)-trans-4-Methylene-2-phenylcyclopentanoic Acid and(−)-trans-4-methylene-2-phenylcyclopentanoic Acid

[1197] Method A:

[1198] The (+)-trans-4-methylene-2-phenylcyclopentanoic acid,(S)-(−)-α-methylbenzylamine salt from Step B (4.7 g) was suspended inmethylene chloride and water and acidified with 2M hydrochloric acid andextracted twice with methylene chloride. The organic layers were eachwashed with brine, dried over sodium sulfate, combined and concentratedin vacuo to give the title (+) acid (3.1 g), [α]_(D)=+101 (MeOH,c=0.135).

[1199] Similarly, the (−)-trans-4-methylene-2-phenylcyclopentanoic acid,(R)-(+)-c-methylbenzylamine salt (6.3 g) was converted to the free(−)-title acid (4.23 g), [α]_(D)=−103 (MeOH, c=0.23).

[1200] Method B:

[1201] Step B1:1-(S)-(((S)-(−)-4-Benzyl-2-oxazolidin-1-yl)carbonyl)-3-methylene-2-(S)-phenylcyclopentane(Higher R_(f)) and1-(R)-(((S)-(−)-4-benzyl-2-oxazolidin-1-yl)carbonyl)-3-methylene-2-(R)-phenylcyclopentane(Lower R_(f))

[1202] A solution of (+−)-trans-4-methylene-2-phenylcyclopentanoic acid(47.5 g, 235 mmol) in ether (1 L) and TEA (36 mL, 260 mmol) was cooledto −10° C. Trimethylacetyl chloride (31.8 mL, 260 mmol) was then addedslowly and after stirring at −10° C. for 10 min, the reaction wasallowed to warm to 10° C. over 1 h. The reaction was then recooled to−60° C.

[1203] To the above solution at −60° C. was added via a cannula asolution of (S)-(−)-4-benzyl-2-oxazolidinone (45.8 g, 260 mmol) in THF(500 mL) which had been treated at −50° C. with 2.5 M n-butyl lithium(103 mL, 257 mmol) and aged at −50° C. for 45 min. The reaction wasallowed to warm to rt over 16 h. The reaction was diluted with ether (1L) and quenched with sat'd aqueous ammonium chloride (1 L). The layerswere separated and the aqueous layer was reextracted with a secondportion of ether. The organic layers were each washed twice with 2Nhydrochloric acid, twice with 1N sodium hydroxide and brine, dried oversodium sulfate, combined and concentrated. The residue was purified bychromatography (20% ethyl acetate in hexanes) to give the twodiastereomeric products, higher R_(f) (18.4 g) and lower R_(f) (17.7 g).

[1204] Step B2: (+)-trans-4-Methylene-2-phenylcyclopentanoic Acid

[1205] A solution of1-(S)-(((S)-(−)4-benzyl-2-oxazolidin-1-yl)carbonyl)-3-methylene-2-(S)-phenylcyclopentane(higher R_(f) product from Step B1) (20.9 g, 58 mmol) in a 3:1 mixtureof THF:water (1 L) was cooled to 5° C. Hydrogen peroxide (30%, 39.5 mL,350 mmol) and lithium hydroxide (4.85 g, 106 mmol) were added and thereaction was stirred for 3.5 h. The excess peroxide was quenched bydropwise addition of sodium sulfite (60 g) in water (1 L) over 1.5 hwhile maintaining the temperature below 5° C. After stirring for 2additional hours, most of the THF was removed in vacuo and the aqueouslayer was washed 3 times with methylene chloride. The aqueous layer wasacidified to pH=2 with conc. HCl and reextracted twice with methylenechloride. The organic layers were washed with brine, dried andconcentrated to give the (+) title product, [α]_(D)=+100.5 (MeOH,c=0.207).

[1206] Step D:(+)-trans-1-Hydroxymethyl-4-methylene-2-phenylcyclopentane and(−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane

[1207] Method A:

[1208] A solution of (+)-trans-4-methylene-2-phenylcyclopentanoic acidfrom Step C (4.15 g, 20.5 mmol) in THF (100 mL) under nitrogen wascooled to −7° C. and 1M LAH in THF (31 mL, 31 mmol) was added dropwiseover 15. The reaction was allowed to warm to rt over 16 h. The excessLAH was quenched by dropwise addition of acetone and the reaction wasthen poured into dilute aq. HCl. The mixture was extracted twice withether and the organic layers were washed with brine, dried over sodiumsulfate, combined and concentrated. The residue was purified by FC (20%ethyl acetate in hexanes) to afford the title (+) product (3.93 g),[α]_(D)=+50 (MeOH, c=0.20).

[1209] Similarly, the (−)-trans-4-methylene-2-phenylcyclopentanoic acidfrom Step C (4.23 g) was converted to the title (−) alcohol (3.75 g),[α]_(D)=−51 (MeOH, c=0.2).

[1210] Method B:

[1211] Prep-HPLC of (+−)-trans-4-methylene-2-phenylcyclopentanoic fromexample 1, Step B using a Chiracel OD column (5-10% isopropanol inhexanes) affords good separation of the title (−) enantiomer as thefirst eluting band and the (+) enantiomer as the second eluting band.

[1212] Step E:(+)-trails-1-t-Butyldimethylsilyloxymethyl4-methylene-2-phenylcyclopentaneand(−)-trans-1-t-butyldimethylsilyloxymethyl-4-methylene-2-phenylcyclopentane

[1213] To a solution of(+)-trans-1-hydroxymethyl4-methylene-2-phenylcyclopentane from Step D(3.9 g, 21 mmol) in methylene chloride (50 mL) was addedt-butyldimethylsilyl chloride (4.7 g, 31 mmol) and DIPEA (7.3 mL, 42mmol). The reaction was stirred at rt for 16 h, poured into dilute aq.HCl and extracted twice with ether. The organic layers were washed withbrine, dried over sodium sulfate, combined and concentrated. The residuewas purified by FC (100% hexanes) to afford the title product (5.6 g) asa oil, [α]_(D)=+42.3 (MeOH, c=0.18).

[1214] Similarly,(−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step D(3.75 g) was converted to the title (−) silylether (5.5 g),[α]_(D)=−44.4 (MeOH, c=0.18).

[1215] Step F: (+)-trans-1-Hydroxymethyl-4-oxo-2-phenylcyclopentane and(−)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane

[1216] Method A:

[1217] A solution of(+)-trans-1-t-butyldimethylsilyloxymethyl-4-methylene-2-phenylcyclopentanefrom Step E (4.6 g, 15 mmol) in methanol (100 mL) was cooled to −70° C.in a dry-ice acetone bath and ozone was bubbled through until a bluecolor persisted which was discharged with a stream of nitrogen.Dimethylsulfide (10 mL) was added and after 15 min, the reaction wasallowed to warm to rt over 16 h. Since by TLC (20% ethyl acetate inhexanes) indicated that there was significant loss of the silyl as wellas dimethylketal formation, the methanol was mostly remove in vacuo. Theresidue was diluted with water and treated with sulfuric acid (6 mL) andstirred for 2 h. The mixture was extracted twice with ethyl acetate andthe organic layers were washed with brine (containing some sodiumbicarbonate), dried over sodium sulfate, combined and concentrated. Theresidue was purified by FC (15-30% ethyl acetate in hexanes) to give the(+) title ketone/alcohol (2.87 g), [α]_(D)=−96 (MeOH, c=0.2).

[1218] Similarly,(−)-trans-1-t-butyldimethylsilyloxymethyl-4-methylene-2-phenylcyclopentanefrom Step E (4.4 g) was converted to the title (−) ketone/alcohol (2.8g), [α]_(D)=+97 (MeOH, c=0.2).

[1219] Method B:

[1220] The title compounds can also be obtained directly from(+)-trans-1-hydroxymethyl4-methylene-2-phenylcyclopentane and(−)-trans-1-hydroxymethyl4-methylene-2-phenylcyclopentane by ozonolysisas above. Thus,(+)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane (3.7 gm, 20mmol) afforded from (+)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane(3.5 g).

[1221] Step G:1-(S)-Benzylamino-3-(S)-hydroxymethyl-4-(S)-phenylcyclopentane and1-(R)-benzylamino-3-(S)-hydroxymethyl-4-(S)-phenylcyclopentane

[1222] To a solution of(+)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane from Step F (1.19g, 6.3 mmol) in 1,2-dichloroethane (25 mL) was added benzylamine (1.3mL, 12 mmol) and acetic acid (0.75 mL, 13 mmol). After 10 min, sodiumtriacetoxyborohydride (2.65 g, 12.5 mmol) was added in portions and thereaction was stirred at rt for 16 h. The reaction was quenched intodilute aq. sodium carbonate and the mixture was extracted twice withethyl acetate. The organic layers were washed with brine, dried oversodium sulfate, combined and concentrated. The residue was purified byFC (5-10% methanol in methylene chloride) to separate the title products(1.6 g) as a mixture of C-1 isomers.

[1223] Step H:1-(S)-t-Butoxycarbonylamino-3-(S)-hydroxymethyl-4-(S)-phenylcyclopentane(Higher R_(f) isomer) and1-(R)-t-butoxycarbonylamino-3-(S)-hydroxymethyl-4-(S)-phenylcyclopentane(Lower R_(f) Isomer)

[1224] To a solution of1-(S)-benzylamino-3-(S)-hydroxymethyl-4-(S)-phenylcyclopentane and1-(R)-benzylamino-3-(S)-hydroxymethyl-4-(S)-phenylcyclopentane from StepG (1.6 g,-5.6 mmol) in methanol (40 mL) was added 20% palladiumhydroxide (300 mg, 50% by wt water) and ammonium formate (7.0 g, 111mmol). The reaction was heated at 60° C. for 6 h and rt for 16 h. Thereaction was filtered and concentrated. The residue was taken up inwater and the aqueous layer was made basic with 2N sodium hydroxide andextracted twice with methylene chloride. The organic layers were washedwith brine, dried over sodium sulfate, combined and concentrated toafford crude amino-alcohol.

[1225] The above product was taken up in methylene chloride (25 mL),cooled in an ice bath and DIPEA (2.9 mL, 17 mmol) and di-t-butyldicarbonate (1.28 g, 5.8 mmol) were added. After 16 h, the reaction waspoured into dilute aq. HCl and extracted twice with methylene chloride.The organic layers were washed with brine, dried over sodium sulfate,combined and concentrated. The residue was purified by FC (30-40% ethylacetate in hexanes) to afford separation of the two title compounds.

[1226] Higher R_(f):

[1227]¹H NMR (CDCl₃) δ: 1.43 (s, 9H), 1.45 (m, 1H), 1.9-2.1 (m, 2H),2.17 (m, 1H), 2.40 (m, 1H), 3.01 (q, 1H), 3.59 (dABq, 2H), 4.20 (br m,1H), 5.00 (br s, 1H), 7.15-7.3 (m, 5H).

[1228] Lower R_(f):

[1229]¹H NMR (CDCl₃) δ: 1.43 (s, 9H), 1.58 (ddd, 1H), 1.78.1 (ddd, 1H),2.02 (m, 1H), 2.29 (m, 1H), 2.47 (ddd, 1H), 2.76 (ddd, 1H), 3.54 (dABq,2H), 4.06 (br m, 1H), 4.62 (br s, 1H), 7.15-7.3 (m, 5H).

[1230] Step I:1-(S)-t-Butoxycarbonylamino-3-(S)-formyl-4-(S)-phenylcyclopentane(Higher R_(f) Isomer) and1-(R)-t-butoxycarbonylamino-3-(S)-formyl-4-(S)-phenylcyclopentane (LowerR_(f) Isomer)

[1231] To a solution of oxalyl chloride (0.145 mL, 1.67 mmol) inmethylene chloride (10 mL) at −70° C. was added dropwise DMSO (0.24 mL,3.3 mmol). After 15 min, a solution of1-(S)-t-butoxycarbonylamino-3-(S)-hydroxymethyl-4-(S)-phenylcyclopentane(Higher R_(f) isomer from Step H) (194 mg, 0.66 mmol) in methylenechloride (5 mL) was added. The reaction was stirred at −70° C. for 1.5 hand then DIPEA (1.2 mL, 6.6 mmol) in methylene chloride (5 mL) was addeddropwise over 5 min. After a further 10 min, the mixture was allowed towarm to rt for 1 h and then diluted with methylene chloride and pouredinto dilute aq. HCl. The layers were separated. The aq. layer wasreextracted with a second portion of methylene chloride and the organiclayers were each washed with brine, dried over sodium sulfate, combinedand concentrated in vacuo. The residue was purified by FC (15% ethylacetate in hexanes) to give the title product (155 mg) after vacuumdrying.

[1232] Using essentially the same procedure as above, material derivedfrom the lower isomer from Step H (0.189 g, 0.6 mmol) was also convertedto the lower R_(f) title compound (175 mg).

[1233] Step J:1-(S)-(t-Butoxycarbonylamino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane(Higher R_(f) Isomer) and1-(R)-(t-butoxycarbonylamino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane(Lower R_(f) Isomer)

[1234] To a solution of1-((S)-(t-butoxycarbonylamino)-3-(S)-(carbonyl)-4-(S)-phenylcyclopentane(from Step I, derived from Higher R_(f) isomer in Step H) (155 mg, 0.54mmol) in 1,2-dichloroethane (5 mL) was added4-(N-(4-nitrobenzyloxycarbonyl)(N-allyl)amino)piperidine hydrochloride(210 mg, 0.59 mmol) and DIPEA (0.12 mL, 0.64 mmol). After 15 min, sodiumtriacetoxyborohydride (230 mg, 1.1 mmol) was added and the reaction wasstirred at rt for 16 h. The reaction was diluted with methylenechloride, quenched with aq. sodium carbonate and extracted 3 times withmethylene chloride. The organic layers were each washed with brine,dried over sodium sulfate, combined and concentrated in vacuo. Theresidue was purified by Prep TLC eluting with 5% methanol in methylenechloride to give the title product (280 mg) as the free amine.

[1235] MS (NH₃/ESI): m/z 593 (M+1).

[1236] Using essentially the same procedure as above, material derivedfrom the lower isomer from Step H-I (0.175 g, 0.6 mmol) was alsoconverted to the lower R_(f) title compound (275 mg).

[1237] Step K:1-(S)-(Amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentaneDi-Hydrochloride Salt (Higher R_(f) Isomer) and1-(R)-(amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentaneDi-Hydrochloride Salt (Lower R_(f) Isomer)

[1238] A solution of hydrogen chloride (4.6 mmol) in methanol wasprepared by addition of acetyl chloride (0.325 mL, 4.6 mmol) to methanol(10 mL) and aging for 15 min. To this was added1-(S)-(t-butoxycarbonylamino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane(Higher R_(f) isomer from Step J) (270 mg, 0.46 mmol). After 16 h, thevolatiles were removed in vacuo to dryness to give the title compound asthe di-hydrochloride salt (248 mg).

[1239] Using essentially the same procedure as above, material derivedfrom the lower isomer from Step H-J (0.250 g, 0.42 mmol) was alsoconverted to the lower R_(f) title compound (235 mg).

[1240] Step L:N-(1-(S)-3-(S)-((4-(N-(4-Nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucine (Isomer 6B) andN-(1-(S)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Isomer 7H) di-TFA Salts

[1241] To a solution of1-(S)-(amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentanedi-hydrochloride salt (derived from the higher R_(f) isomer in StepsH-K) (20 mg, 0.045 mmol), 4-methyl-2-oxo-valeric acid (15 mg, 0.11 mmol)and DIPEA (0.016 mL, 0.09 mmol) in 1,2-dichloroethane (2 mL) was addedsodium triacetoxyborohydride (29 mg, 0.135 mmol). The reaction wasstirred at 50° C. for 10 h and then at rt for another 16 h. It was thenquenched with aq sodium carbonate and extracted three times with ethylacetate. The organic layers were each washed with brine, dried oversodium sulfate, combined and concentrated in vacuo. The residue waspurified by Prep TLC eluting with 10% methanol in methylene chloride togive the title products (8 mg) as a mixture of the free amines. HPLCanalysis as in

EXAMPLE 6 and 7 gave only a single band corresponding to Isomers B (andenantiomeric Isomer F) and H (and enantiomeric Isomer D) which co-elute.

[1242] HPLC/MS (ESI): m/z 593 (M+1).

EXAMPLE 9

[1243]N-(1-(R)-3-(S)-((4-(N-(4-Nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucine(Isomer 7E) andN-(1-(R)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Isomer 6C) Di-TFA Salts

[1244] Using essentially the same procedure as in Example 8, Step L, butsubstituting1-(R)-(amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentanedi-hydrochloride salt (derived from the lower R_(f) isomer in Steps H-K)(20 mg, 0.045 mmol), the two title compounds were prepared. HPLCanalysis of the crude products as in Example 6 and 7 indicated twopeaks. In this case the diastereomers were separable on Prep TLC (10%methanol in methylene chloride). HPLC analysis as in Example 6 and 7 nowgave only a single peak for each sample from the Prep TLC. The higherband corresponded to Isomer E (and enantiomeric Isomer A) and the lowerband corresponded to Isomer C (and enantiomeric Isomer G) which aredistinct in the HPLC. The di-TFA salts were prepared by evaporation from0.5% TFA in acetonitrile.

[1245] Higher Isomer E: HPLC/MS (ESI): m/z 593 (M+1).

[1246] Lower Isomer C: HPLC/MS (ESI): m/z 593 (M+1).

EXAMPLE 10

[1247] Using essentially the same procedure as in Example 6, Steps E toG, but substituting 4-(3-(4-fluorophenyl)prop-1-yl)piperidinehydrochloride in Step E and L-valine t-butyl ester hydrochloride in StepF, the following diastereomers can be obtained after a combination ofPrep TLC and HPLC separation.

[1248]N-(1-(S)-3-(R)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-valinedi-TFA salt (Isomer A),

[1249]N-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-valinedi-TFA salt (Isomer B),

[1250]N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-valinedi-TFA salt (Isomer C)

[1251]N-(1-(R)-3-(R)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-valinedi-TFA salt (Isomer D)

EXAMPLE 11

[1252] Using essentially the same procedure as in Example 6, Steps E toG, but substituting 4-(3-(4-fluorophenyl)prop-1-yl)piperidinehydrochloride (from Procedure 9) in Step E and L-leucine t-butyl esterhydrochloride in Step F, the following diastereomers can be obtainedafter a combination of Prep TLC and HPLC separation.

[1253]N-(1-(S)-3-(R)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-leucinedi-TFA salt (Isomer A),

[1254]N-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucinedi-TFA salt (Isomer B),

[1255]N-(-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-isoleucinedi-TFA salt (Isomer C)

[1256]N-(1-(R)-3-(R)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-leucinedi-TFA salt (Isomer D)

EXAMPLE 12

[1257] Using essentially the same procedure as in Example 6, Steps E toG, but substituting 4-(3-(4-fluorophenyl)prop-1-yl)piperidinehydrochloride (from Procedure 9) in Step E and L-phenylglycine t-butylester hydrochloride in Step F, the following diastereomers can beobtained after a combination of Prep TLC and HPLC separation.

[1258]N-(1-(S)-3-(R)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(R)phenylcyclopent-1-yl)-1-phenylglycinedi-TFA salt (Isomer A),

[1259]N-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-phenylglycinedi-TFA salt (Isomer B),

[1260]N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-phenylglycinedi-TFA salt (Isomer C)

[1261]N-(1-(R)-3-(R)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-phenylglycinedi-TFA salt (Isomer D)

EXAMPLE 13

[1262] Using essentially the same procedure as in Example 6, Steps E toG, but substituting 4-(3-(4-fluorophenyl)prop-1-yl)piperidinehydrochloride (from Procedure 9) in Step E and L-cyclohexylglycinet-butyl ester hydrochloride in Step F, the following diastereomers canbe obtained after a combination of Prep TLC and HPLC separation.

[1263]N-(1-(S)-3-(R)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer A),

[1264] HPLC/MS (ESI): m/z 633 (M+1).

[1265]N-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer B),

[1266] HPLC/MS (ESI): m/z 633 (M+1).

[1267]N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer C)

[1268] HPLC/MS (ESI): m/z 633 (M+1).

[1269]N-(1-(R)-3-(R)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer D)

[1270] HPLC/MS (ESI): m/z 633 (M+1).

EXAMPLE 14

[1271] Using essentially the same procedures as in Example 6, Steps E toG, but substituting 4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidinehydrochloride (from Procedure 1) in Step E and L-cyclohexylglycinet-butyl ester hydrochloride in Step F and TFA in place of HCl in etherin Step G, the following diastereomers can be obtained after acombination of Prep TLC and HPLC separation.

[1272]N-(1-(S)-3-(R)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer A),

[1273]N-(1-(S)-3-(S)-((4-(3-benzyl-1-ethyl-H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer B),

[1274]N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-cyclohexylglycine di-TFA salt (Isomer C)

[1275]N-(1-(R)-3-(R)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer D)

EXAMPLE 15

[1276] Using essentially the same procedures as in Example 6, Steps E toG, but substituting 4-(4-fluorophenyl)piperidine hydrochloride (fromProcedure 9) in Step E and L-cyclohexylglycine t-butyl esterhydrochloride in Step F and TFA in place of HCl in ether in Step G, thefollowing diastereomers can be obtained after a combination of Prep TLCand HPLC separation.

[1277]N-(1-(S)-3-(R)-((4-(4-fluorophenyl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer A),

[1278]N-(1-(S)-3-(S)-((4-(4-fluorophenyl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer B),

[1279]N-(1-(R)-3-(S)-((4-(4-fluorophenyl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-cyclohexylglycinedi-TFA salt (Isomer C)

[1280]N-(1-(R)-3-(R)-((4-(4-fluorophenyl)piperidin-1-yl)methyl)-4-(R)-phenylcyclopent-1-y])-1-cyclohexylglycinedi-TFA salt (Isomer D)

EXAMPLE 16

[1281]N-(1-(R)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA salt andN-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt

[1282] Step A:(1-(R)-3-(S)-(Hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Higher R_(f)) and(1-(S)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Lower R_(f))

[1283] Method A:

[1284] To a solution of(+)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane from Example 8,Step F (250 mg, 1.32 mmol), D-leucine t-butyl ester hydrochloride (370mg, 2.0 mmol) and DIPEA (0.36 mL, 2.0 mmol) in 1,2-dichloroethane (10mL) was added sodium triacetoxyborohydride (840 mg, 4.0 mmol). Thereaction was stirred at rt for 4 h and was then quenched with aq sodiumcarbonate and extracted three times with ethyl acetate. The organiclayers were each washed with brine, dried over sodium sulfate, combinedand concentrated in vacuo. The residue was purified by FC eluting with agradient of 5-25% ethyl acetate in hexanes to give the higher R_(f)1-(R) title compound as the major product (280 mg) and the lower R_(f)1-(S) as the minor product (160 mg mixed fractions).

[1285] Method B:

[1286] To a solution of(+)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane from Example 8,Step F (3.3 g, 16 mmol) in methylene chloride (100 mL) was addedt-butyldimethylsilyl chloride (11 g, 49 mmol) and DIPEA (22 mL, 74mmol). The reaction was stirred at rt for 16 h, poured into dilute aq.HCl and extracted twice with ether. The organic layers were washed withbrine, dried over sodium sulfate, combined and concentrated. The residuewas purified by FC (5% ethyl acetate in hexanes) to afford of(+)-trans-1-t-butyldimethylsilyloxymethyl-4-oxo-2-phenylcyclopentane(6.3 g) as a oil, [α]_(D)=+97 (MeOH, c=0.2).

[1287] To a solution of(+)-trans-1-t-butyldimethylsilyloxymethyl-4-oxo-2-phenylcyclopentanefrom above (1.0 g, 3.28 mmol), D-leucine t-butyl ester hydrochloride(2,2 g, 3.0 mmol) and DIPEA (1.8 mL, 10.2 mmol) in 1,2-dichloroethane(20 mL) was added sodium triacetoxyborohydride (2.1 g, 10 mmol). Thereaction was stirred at rt for 5 h and was then quenched with aq sodiumcarbonate and extracted three times with ethyl acetate. The organiclayers were each washed with brine, dried over sodium sulfate, combinedand concentrated in vacuo. The residue was purified by FC eluting with5% ethyl acetate in hexanes to give the higher R_(f) 1-(R) titlecompound as the minor product and the lower R_(f) 1-(S) as the majorproduct (1.35 g as a mixture).

[1288] To a solution of the above product (1.35 g, 2.85 mmol) in THF (10mL) was added 1M TBAF in THF (4.3 mL, 4.3 mmol). The reaction wasstirred at rt for 16 h and the concentrated. The residue was purified byFC eluting with 20-25% ethyl acetate in hexanes to give the higher R_(f)1-(R) title compound as the minor product (33 mg pure) and the lowerR_(f) 1-(S) as the major product (202 mg pure, 0.70 g as a mixture).

[1289] Step B:(1-(R)-3-(S)-(Formyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine (HigherR_(f)) and (1-(S)-3-(S)-(carbonyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Lower R_(f))

[1290] Method A:

[1291] To a solution of oxalyl chloride (0.100 mL, 1.1 mmol) inmethylene chloride (20 mL) at −70° C. was added dropwise DMSO (2.2 mL,5.0 mmol). After 15 min, a solution of(1-(R)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(Higher R_(f) from Step A, Method A) (160 mg, 0.44 mmol) containing 1eq. of 1M HCl in ether in methylene chloride (5 mL) was added. Thereaction was stirred at −70° C. for 1.5 h and then DPEA (0.77 mL, 4.5mmol) in methylene chloride (5 mL) was added dropwise over 5 min. Aftera further 10 min, the mixture was allowed to warm to rt for 1 h and thendiluted with methylene chloride and poured into dilute aq. HCl. Thelayers were separated. The aq. layer was reextracted with a secondportion of methylene chloride and the organic layers were each washedwith brine, dried over sodium sulfate, combined and concentrated invacuo. The residue was purified by FC (20% ethyl acetate in hexanes) togive the higher R_(f) title product (38 mg) after vacuum drying.

[1292] Method B:

[1293] To a solution of(1-(R)-3-(S)-(hydroxymethyl)4-(S)-phenylcyclopent-1-yl)-D-leucine(mixture of higher and lower R_(f) from Step A, Method A) (142 mg, 0.39mmol) in methylene chloride (10 mL) was added TPAP (6.9 mg, 0.020 mmol)and N-methylmorholine (70 mg, 0.60 mmol). The reaction was stirred undernitrogen at rt for 1 h and was then concentrated. The residue waspurified by FC (25% ethyl acetate in hexanes) to give the title products(108 mg) after vacuum drying.

[1294] Step C:N-(1-(R)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucinet-butyl Ester (Higher R_(f)) andN-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucinet-butyl Ester (Lower R_(f))

[1295] To a solution of(1-(R)-3-(S)-(formyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine (higherR_(f)) and (1-(S)-3-(S)-(formyl)-4-(S)-phenylcyclopent-1-yl)-D-leucine(lower R_(f)) (from Step B, Method B) (9 mg, 0.025 mmol) in1,2-dichloroethane (1 mL) was added4-(3-(4-fluorophenyl)prop-1-yl)piperidine hydrochloride (from Procedure9) (8 mg, 0.032 mmol) and DIPEA (0.006 mL, 0.033 mmol). After 15 min,sodium triacetoxyborohydride (11 mg, 0.051 mmol) was added and thereaction was stirred at rt for 16 h. The reaction was diluted withmethylene chloride, quenched with aq. sodium carbonate and extracted 3times with methylene chloride. The organic layers were each washed withbrine, dried over sodium sulfate, combined and concentrated in vacuo.The residue was purified by Prep TLC eluting with 60% ethyl acetate inhexanes to give the title products as the free amines.

[1296] (Each isomer): HPLC/MS (ES): m/z 565 (M+1).

[1297] Step D:N-(1-(R)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt (Derived from Higher R_(f)) andN-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucinedi-TFA Salt (Derived from Lower R_(f))

[1298] Each the products from Step C were taken up in TFA (5 mL) andaged at rt for 16 h. The volatiles were removed under a stream ofnitrogen to afford the title products as the di-TFA salts (4 mg and 6mg).

[1299] (Each isomer): HPLC/MS (ES): m/z 509 (M+1).

EXAMPLE 17

[1300]N-(1-(R)-3-(S)-((4-(3-(Benzofurazan-5-yl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(benzofurazan-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt

[1301] Using essentially the same procedures as in Example 16, Step Cand D, but substituting 4-(3-(benzofurazan-5-yl)prop-1-yl)piperidinehydrochloride (from Procedure 6) in Step C, the two diastereomeric titlecompounds were prepared.

[1302] (Each isomer): HPLC/MS (ESI): m/z 533 (M+1).

EXAMPLE 18

[1303]N-(1-(R)-3-(S)-((4-(3-(4-Cyano-3-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-(4-cyano-3-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt

[1304] Using essentially the same procedures as in Example 16, Step Cand D, but substituting4-(3-(4-cyano-3-fluorophenyl)prop-1-yl)piperidine hydrochloride (fromProcedure 8) in Step C, the title compounds can be prepared.

EXAMPLE 19

[1305]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt

[1306] D-leucine

[1307] Using essentially the same procedures as in Example 16, Step Cand D, but substituting 4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidinehydrochloride (from Procedure 1) in Step C, the title compounds can beprepared.

EXAMPLE 20

[1308]N-(1-(R)-3-(S)-((4-(N-(Propyl)-N-(pyrrimidin-2-yl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(N-(propyl)-N-(pyrrimidin-2-yl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt

[1309] Using essentially the same procedures as in Example 16, Step Cand D, but substituting 4-(N-(propyl)-N-(pyrimidin-2-yl)amino)piperidinehydrochloride (from Procedure 13) in Step C, the title compounds can beprepared.

EXAMPLE 21

[1310]N-(1-(R)-3-(S)-((4-(4-Fluorophenyl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(4-fluorophenyl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-leucinedi-TFA Salt

[1311] Using essentially the same procedures as in Example 16, Step Cand D, but substituting 4-(4-fluorophenyl)piperidine hydrochloride inStep C, the title compounds can be prepared.

EXAMPLE 22

[1312]N-(1-(R)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-TFA Salt

[1313] Using essentially the same procedures as in Example 16, Step A toD, but substituting D-cyclohexylglycine t-butyl ester hydrochloride inStep A and 4-(3-(4-fluorophenyl)prop-1-yl)piperidine hydrochloride (fromProcedure 9) in Step C, the title compounds were prepared.

[1314] (Each isomer): HPLC/MS (ESI): m/z 535 (M+1).

EXAMPLE 23

[1315]N-(1-(R)-3-(S)-((4-(3-(4-Cyano-3-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-(4-cyano-3-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-TFA Salt

[1316] Using essentially the same procedures as in Example 16, Step A toD, but substituting D-cyclohexylglycine t-butyl ester hydrochloride inStep A and 4-(3-(4-cyano-3-fluorophenyl)prop-1-yl)piperidinehydrochloride (from Procedure 8) in Step C, the title compounds wereprepared.

[1317] (Each isomer): HPLC/MS (ESI): m/z 560 (M+1).

EXAMPLE 24

[1318]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-TFA Salt

[1319] Using essentially the same procedures as in Example 16, Step A toD, but substituting D-cyclohexylglycine t-butyl ester hydrochloride inStep A and 4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidine hydrochloride(from Procedure 1) in Step C, the title compounds were prepared.

[1320] (Each isomer): HPLC/MS (ESI): m/z 583 (M+1).

EXAMPLE 25

[1321]N-(1-(R)-3-(S)-((4-(N-(Propyl)-N-(pyrrimidin-2-yl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycinedi-TFA Salt andN-(1-(S)-3-(S)-((4-(N-(propyl)-N-(pyrrimidin-2-yl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-TFA Salt

[1322] Using essentially the same procedures as in Example 16, Step A toD, but substituting D-cyclohexylglycine t-butyl ester hydrochloride inStep A and 4-(N-(propyl)-N-(pyrrimidin-2-yl)amino)piperidinehydrochloride (from Procedure 13) in Step C, the title compounds wereprepared.

[1323] (Each isomer): HPLC/MS (ESI): m/z 534 (M+1).

EXAMPLE 26

[1324]N-(1-(R)-3-(S)-((4-(4-Fluorophenyl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(4-fluorophenyl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycinedi-TFA Salt

[1325] Using essentially the same procedures as in Example 16, Step A toD, but substituting D-cyclohexylglycine t-butyl ester hydrochloride inStep A and 4-(4-fluorophenyl)piperidine hydrochloride in Step C, thetitle compounds were prepared.

[1326] (Each isomer): HPLC/MS (ESI): m/z 493 (M+1).

EXAMPLE 27

[1327]N-(1-(R)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclobutylalanineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclobutylalanineDi-TFA Salt

[1328] Using essentially the same procedures as in Example 16, Step A toD, but substituting D/L-cyclobutylalanine t-butyl ester hydrochloride inStep A and 4-(3-(4-fluorophenyl)prop-1-yl)piperidine hydrochloride (fromProcedure 9) in Step C, the title compounds can be prepared.

EXAMPLE 28

[1329]N-(1-(R)-3-(S)-((4-(3-(4-Cyano-3-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D/L-cyclobutylalanineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-(4-cyano-3-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D/L-cyclobutylalanineDi-TFA Salt

[1330] Using essentially the same procedures as in Example 16, Step A toD, but substituting D/L-cyclobutylalanine t-butyl ester hydrochloride inStep A and 4-(3-(4-cyano-3-fluorophenyl)prop-1-yl)piperidinehydrochloride (from Procedure 8) in Step C, the title compounds can beprepared.

EXAMPLE 29

[1331]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D/L-cyclobutylalanineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D/L-cyclobutylalanineDi-TFA Salt

[1332] Using essentially the same procedures as in Example 16, Step A toD, but substituting D/L-cyclobutylalanine t-butyl ester hydrochloride inStep A and 4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidine hydrochloride(from Procedure 1) in Step C, the title compounds were prepared.

EXAMPLE 30

[1333]N-(1-(R)-3-(S)-((4-(N-(Propyl)-N-(pyrrimidin-2-yl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D/L-cyclobutylalanineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(N-(propyl)-N-(pyrrimidin-2-yl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D/L-cyclobutylalaninedi-TFA Salt

[1334] Using essentially the same procedures as in Example 16, Step A toD, but substituting D/L-cyclobutylalanine t-butyl ester hydrochloride inStep A and 4-(N-(propyl)-N-(pyrrimidin-2-yl)amino)piperidinehydrochloride (from Procedure 13) in Step C, the title compounds can beprepared.

EXAMPLE 31

[1335]N-(1-(R)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclopropylalanineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclopropylalanineDi-TFA Salt

[1336] Using essentially the same procedures as in Example 16, Step A toD, but substituting D-cyclopropylalanine t-butyl ester hydrochloride inStep A and 4-(3-(4-fluorophenyl)prop-1-yl)piperidine hydrochloride inStep C, the title compounds can be prepared.

EXAMPLE 32

[1337] N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)pipeidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclopropylalanineDi-TFA Salt andN-(1-(S)-3-(S)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclopropylalanineDi-TFA Salt

[1338] Using essentially the same procedures as in Example 16, Step A toD, but substituting D-cyclopropylalanine t-butyl ester hydrochloride inStep A and 4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidine hydrochloride(from Procedure 1) in Step C, the title compounds were prepared.

EXAMPLE 33

[1339]N-(1-(R)-3-(S)-((4-(3-(Benzofurazan-5-yl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycineDi-Hydrochloride Salt

[1340] Using essentially the same procedure as in Example , Steps A toD, but substituting D-cyclohexylglycine t-butyl ester hydrochloride inStep A and 4-(3-(benzofurazan-5-yl)prop-1-yl)piperidine (from Procedure5) in Step C, the title compound was prepared.

[1341] HPLC/MS (ESI): m/z 559 (M+1).

EXAMPLE 34

[1342]N-(1-(R)-3-(S)-((4-(3-(4-Flurophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-leucineDi-Hydrochloride Salt

[1343] Using essentially the same procedure as in Example 16, Steps A toD, but substituting L-leucine t-butyl ester hydrochloride in Step A and4-(3-(4-flurophenyl)prop-1-yl)piperidine in Step F, the title compoundwas prepared.

[1344] HPLC/MS (ESI): m/z 509 (M+1).

EXAMPLE 35

[1345]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclohexylglycineTri-Hydrochloride Salt

[1346] Step A: Methyl(+−)-trans-4-methylene-2-(3-fluorophenyl)cyclopentanoate

[1347] A mixture of methyl trans-3-fluorocinnamate (41.25 g, 229 mmol),tetrakis(triphenylphosphine) palladium(0) (18.5 g, 16 mmol),1,2-bis(diphenylphosphino)ethane (5.5 g, 13.7 mmol) and2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (42.66 g, 229 mmol) inTHF (300 mL) under nitrogen was heated to reflux for 6 h and thenstirred at rt for 16 h. The reaction was diluted with hexane andfiltered to remove yellow precipitate. The volatiles were then removedin vacuo and the residue was purified by FC (3 to 5% ethyl acetate inhexanes) to afford the title compound (45 g).

[1348]¹H NMR (CDCl₃) δ: 2.52 (m, 1H), 2.68 (m, 1H), 2.8-2.9 (m, 2H),2.95 (ddd, 1H), 3.45 (ddd, 1H), 3.63 (s, 3H), 4.96 (m, 2H), 6.9-7.0 (m,2H), 7.03 (d, 1H), 7.2-7.3 (m, 1H).

[1349] Step B: (+−)-trans-4-Methylene-2-(3-fluorophenyl)cyclopentanoicAcid

[1350] To a solution of methyl(+−)-trans-4-methylene-2-(3-fluoro)phenylcyclopentanoate prepared as inExample 35, Step A (47 g, 200 mmol) in methanol (500 mL) was added 5Nsodium hydroxide (200 mL, 1000 mmol). The reaction was stirred at rt for60 h then concentrated in vacuo. The residue was taken up in water,acidified with 2M hydrochloric acid and extracted twice with methylenechloride. The organic layers were each washed with brine, dried oversodium sulfate, combined and concentrated in vacuo to give the crudetitle acid (40.8 g) which was used directly in Step C.

[1351] Step C:(+)-trans-1-Hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane and(−)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane

[1352] A solution of(+−)-trans-4-methylene-2-(3-fluorophenyl)cyclopentanoate (5.2 g, 23.6mmol) from Step B in THF (100 mL) was cooled to 0° C. under nitrogen and1M lithium aluminum hydride (LAH) in THF (35.4 mL) was added dropwiseover 10 min. The reaction was stirred at rt for 16 h, the excess LAH wasquenched by dropwise addition of acetone and the reaction was thenpoured into dilute aq. HCl. The mixture was extracted twice with etherand the organic layers were washed with brine, dried over sodiumsulfate, combined and concentrated. The residue was purified by FC (25%ethyl acetate in hexanes) to afford the racemic title product (4.1 g) asa an oil. Chiral Prep HPLC on a 2 cm×25 cm Chiracel OD column elutingwith 5% isopropanol in hexanes (25 injections) afforded the(−)-enantiomer, [α]_(D)=−45.5 (MeOH, c=0.9), as the first eluting peak(R_(t)=17.5 min) and the (+)-enantiomer (1.87 g), [α]_(D)=+45.0 (MeOH,c=1.0), as the second peak (R_(t)=22.0 min).

[1353]¹H NMR (CDCl₃) δ: 2.2-2.35 (m, 2H), 2.5 (m, 1H), 2.65-2.85 (m,2H), 2.9 (m, 1H), 3.51 and 3.68 (dABq, 2H), 4.93 (m, 2H), 6.9-7.0 (m,2H), 7.06 (d, 1H), 7.3-7.4 (m, 1H).

[1354] Step D:(+)-trans-3-Hydroxymethyl-4-(3-fluorophenyl)cyclopentanone

[1355] A solution of(+)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentanefrom Step C (1.87 g, 9.0 mmol) in methanol (75 mL) was cooled in a dryice/acetone bath and ozone was bubbled into the solution until the bluecolor persisted. The excess ozone was removed with a stream of nitrogenand then dimethylsulfide (5 mL) was added. After 10 min, the bath wasremoved and the reaction was allowed to warm to rt over 2 h. The mixturewas treated with 10 drops of sulfuric acid (c) in water (2 mL) for 1 hbefore most of the methanol was removed in vacuo. The mixture wasdiluted with water and extracted twice with ethyl acetate and theorganic layers were washed with brine, dried over sodium sulfate,combined and concentrated. The residue was purified by FC (50% ethylacetate in hexanes) to give the title compound (1.87 g) ), [α]_(D)=+132(MeOH, c=1.2),.

[1356]¹H NMR (CDCl₃) δ: 2.3-2.45 (m, 2H), 2.5 (m, 1H), 2.61 and 2.77(dABq, 2H), 2.28 (ddd, 1H), 3.61 and 3.75 (dABq, 2H), 6.9-7.0 (m, 2H),7.06 (d, 1H), 7.3-7.4 (m, 1H).

[1357] Step E:N-(1-(R)-3-(S)-Hydroxymethyl-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycinet-butyl Ester

[1358] To a solution of(+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanone from Step D(500 mg, 2.4 mmol) in 1,2-dichloroethane (25 mL) was addedD-cyclohexylglycine t-butyl ester (0.61 g, 2.88 mmol) and acetic acid(0.15 mL, 2.64 mmol). After 15 min, sodium triacetoxyborohydride (1.0 g,4.8 mmol) was added and the reaction was stirred at rt for 16 h. Thereaction was diluted with methylene chloride, quenched with aq. sodiumcarbonate and extracted 3 times with methylene chloride. The organiclayers were each washed with brine, dried over sodium sulfate, combinedand concentrated in vacuo. The residue was purified by FC eluting with30% ethyl acetate in hexanes to give the product (936 mg) as clean majorhigher R_(f) title compound (425 mg) plus a mixture of C-1 isomers (511mg) as the free amines.

[1359] Step F:N-(1-(R)-3-(S)-Formyl-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycinet-butyl Ester

[1360] To a solution of(1-(R)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycine(higher R_(f) from Step E) (162 mg, 0.4 mmol) in methylene chloride (5mL) was added TPAP (7 mg, 0.020 mmol) and N-methylmorholine (70 mg, 0.60mmol). The reaction was stirred under nitrogen at rt for 1 h and wasthen concentrated. The residue was purified by FC (15% ethyl acetate inhexanes) to give the title product (115 mg) after vacuum drying.

[1361] Step G:N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclohexylglycinet-butyl Ester

[1362] To a solution ofN-(1-(R)-3-(S)-formyl-4-(S)-phenylcyclopent-1-yl)-D-cyclohexylglycinet-butyl ester (13 mg, 0.032 mmol) from Step F in 1,2-dichloroethane (2mL) was added 4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidinehydrochloride (from Procedure 1) (15 mg, 0.035 mmol) and DIPEA (0.012mL, 0.069 mmol). After 15 min, sodium triacetoxyborohydride (14 mg,0.064 mmol) was added and the reaction was stirred at rt for 16 h. Thereaction was diluted with methylene chloride, quenched with aq. sodiumcarbonate and extracted 3 times with methylene chloride. The organiclayers were each washed with brine, dried over sodium sulfate, combinedand concentrated in vacuo. The residue was purified by Prep TLC elutingwith 5% methanol in methylene chloride to give the title product as thefree amine.

[1363] Step H:N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclohexylglycineTri-Hydrochloride Salt

[1364] TheN-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclohexylglycinet-butyl ester from Step F was taken up in TFA (2 mL) and aged at rt for16 h. The volatiles were evaporated under a stream of nitrogen. Theresidue was taken up in methanol and adsorbed onto a 500 mg Varian SCXion-exchange resin cartridge. The resin was eluted with 2×3 mL ofmethanol, then the product was eluted with 2×3 mL of 2M ammonia inmethanol. The product solution was concentrated under nitrogen, then 2volumes of methylene chloride were evaporated to remove methanol andammonia to give the free amine. The hydrochloride salt was prepared bydissolving the free amine in methylene chloride, addition of excess 1Mhydrogen chloride in ether and evaporation to dryness.

[1365] HPLC/MS (ESI): m/z 601 (M+1).

EXAMPLE 36

[1366]N-(1-(R)-3-(S)-((4-(3-(4-Cyano-3-flurophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclohexylglycinedi-hydrochloride Salt

[1367] Using essentially the same procedure as in Example 35, Steps Gand H, but substituting 4-(3-(4-cyano-3-flurophenyl)prop-1-yl)piperidine(from Procedure 8) in Step G, the title compound was prepared.

[1368] HPLC/MS (ESI): m/z 578 (M+1).

EXAMPLE 37

[1369]N-(1-(R)-3-(S)-((4-(5-Benzylpyrazol-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclohex-ylglycinedi-hydrochloride Salt

[1370] Using essentially the same procedure as in Example 35, Steps Gand H, but substituting 4-(5-benzylpyrazol-3-yl)piperidine (fromProcedure 2) in Step G, the title compound can be prepared.

EXAMPLE 38

[1371]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-propyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclohexylglycineTri-Hydrochloride Salt

[1372] Using essentially the same procedure as in Example 35, Steps Gand H, but substituting 4-(5-benzyl-2-propylpyrazol-3-yl)piperidine(from Procedure 15) in Step G, the title compound can be prepared.

EXAMPLE 39

[1373] Using essentially the same procedure as in Example 35, Steps E toG, but substituting the appropriate L- and/or D-aminoacid t-butyl esterin Step E, the following compounds A-D can be prepared.

Example 39A

[1374]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclobutylalanineTri-Hydrochloride Salt

Example 39B

[1375]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclopropylalanineTri-Hydrochloride Salt

Example 39C

[1376]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

Example 39D

[1377]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

EXAMPLE 40

[1378]N-(2-Methylprop-1-yl)-N-(1-(SR)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)glycinedi-hydrochloride salt

[1379] Step A:1-(SR)-Benzyloxycarbonylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) Isomer) and1-(RS)-benzyloxycarbonylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane(Lower R_(f) Isomer)

[1380] Using essentially the same procedure as in Example 1, Step E,1-(SR and RS)-benzylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane(13 g) was converted to the title compounds. Prep LC (30% ethyl acetatein hexanes) afforded pure minor, higher R_(f) product (4.0 g), then amixture and finally pure major, lower R_(f) product (6.6 g).

[1381] Step B:1-(SR)-Benzyloxycarbonylamino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) isomer) and1-(RS)-benzyloxycarbonylamino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Lower R_(f) Isomer)

[1382] To a solution of1-(SR)-benzyloxycarbonylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) isomer from Step A) (3.96 g, 12.2 mmol) in methylenechloride (100 mL) was added DIPEA (6.4 mL, 37 mmol) andt-butyldimethylsilyl chloride (2.0 g, 13.4 mmol). The reaction wasstirred at rt for 16 h when a second portion of t-butyldimethylsilylchloride (1.0 g, 6.7 mmol) was added. After a further 24 h, the reactionwas diluted with methylene chloride and poured into dilute hydrochloricacid. The layers were separated and the organic layer was washed withbrine containing sodium bicarbonate, dried over sodium sulfate andconcentrated. The residue was purified by FC (5 to 40% ethyl acetate inhexanes) to give the title compound (4.7 g). After eluting with 75%ethyl acetate in hexanes, recovered starting material was obtained.

[1383] In a similar way,1-(RS)-benzyloxycarbonylamino-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopentane(lower R_(f) isomer from Step A) (6.6 g, 20.3 mmol) was converted to thelower R_(f) title compound (7.7 g) and recovered starting material.

[1384] Step C:1-(SR)-N-(2-Methylprop-2-en-1-yl)-N-(benzyloxycarbonyl)amino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) Isomer) and1-(RS)-N-(2-methylprop-2-en-1-yl)-N-(benzyloxycarbonyl)amino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Lower R_(f) Isomer)

[1385] To a solution of1-(SR)-benzyloxycarbonylamino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) isomer from Steps A-B) (500 mg, 1.14 mmol) and1-bromo-2-methylprop-2-ene (0.175 mL, 1.7 mmol) in DMF (10 mL) was addedat rt in portions over 10 min 60% sodium hydride in mineral oil (68 mg,1.7 mmol). After 3 h, the reaction was diluted with ether and quenchedinto water. The layers were separated and the organic layer was washedwith brine containing sodium bicarbonate, dried over sodium sulfate andconcentrated. The residue was purified by FC (5 to 10% ethyl acetate inhexanes) to give the title compound (0.32 g).

[1386]¹H NMR (CDCl₃): δ −0.06 (s, 3H), −0.05 (s, 3H), 0.84 (s, 9H), 1.54(s, 3H), 1.65-1.8 (m, 3H), 1.95-2.2 (m, 3H), 2.8-3.0 (M, 1H), 3.3-3.45(m, 1H), 3.45-3.55 (m, 1H), 3.7-3.9 (m, 2H), 4.80 (d, 2H), 5.14 (br s,2H), 7.15 (m, 2H), 7.25 (m, 5H), 7.34 (m, 3H).

[1387] In a similar way,1-(RS)-benzyloxycarbonylamino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(lower R_(f) isomer from Step A-B) (1.0 g, 2.3 mmol) was converted tothe lower R_(f) title compound (0.55 g).

[1388] Step D:1-(SR)-N-(2-Methylprop-1-yl)amino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) Isomer) and1-(RS)-N-(2-methylprop-1-yl)amino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Lower R_(f) Isomer)

[1389] To a solution of1-(SR)-N-(2-methylprop-2-en-1-yl)-N-(benzyloxycarbonyl)amino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) isomer from Steps A-C) (320 mg, 0.65 mmol) in methanol (5mL) was added 10% Pd/C (50 mg) and a drop of DIPEA. The mixture washydrogenated at 40 psi for 2 h. The reaction was filtered and thefiltrate was concentrated. The residue of title compound was useddirectly in Step E.

[1390]¹H NMR (CDCl₃): δ −0.05 (s, 3H), −0.04 (s, 3H), 0.84 (s, 9H), 0.89(s, 3H), 0.91 (s, 3H), 1.35 (ddd, 1H), 1.73 (hept, 1H), 1.93 (m, 2H),2.15 (m, 1H), 2.25 (m, 1H), 2.38 (d, 2H), 2.96 (q, 1H), 3.28 (m, 1H),3.49 (dABq, 2H), 7.15 (m, 3H), 7.24 (m, 2H).

[1391] In a similar way,1-(RS)-N-(2-methylprop-2-en-1-yl)-N-(benzyloxycarbonyl)amino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(lower R_(f) isomer from Step A-C) (0.55 g, 1.1 mmol) was converted tothe lower R_(f) title compound (0.475 g).

[1392] Step E:N-(2-Methylprop-1-yl)-N-(1-(SR)-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Higher R_(f) Isomer) andN-(2-methylprop-1-yl)-N-(1-(RS)-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Lower R_(f) Isomer)

[1393] A solution of1-(SR)-N-(2-methylprop-1-yl)amino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(Higher R_(f) isomer from Steps A-D) (0.65 mmol), t-butyl bromoacetate(125 mg, 0.65 mmol) and DIPEA (1.1 mL, 6.5 mmol) in acetonitrile (15 mL)was stirred at rt for 16 h. The reaction was diluted with aqueous sodiumcarbonate and extracted three times with ethyl acetate. The organiclayers were washed with brine containing sodium bicarbonate, dried oversodium sulfate, combined and concentrated. The residue was purified byFC (50% ethyl acetate in hexanes) to give impure product and recoveredstarting material (135 mg). The impure product fractions were repurifiedby FC (5% ethyl acetate in hexanes) to afford the title higher R_(f)compound (0.13 g). The recovered starting material was recycled usingthe same procedure but doing the reaction at 50° C. for 16 h to affordadditional title compound (140 mg).

[1394]¹H NMR (CDCl₃): δ −0.05 (s, 3H), −0.04 (s, 3H), 0.84 (s, 9H), 0.86(d, 3H), 0.88 (d, 3H), 1.44 (s, 9H), 1.70 (hept, 1H), 1.95 (m, 1H), 2.00(m, 1H), 2.08 (m, 2H), 2.38 (dABq, 2H), 2.90 (m, 1H), 3.26 (ABq, 2H),3.49 (dABq, 2H), 3.5-3.6 (m, 1 H), 7.15 (m, 3H), 7.24 (m, 2H).

[1395] In a similar way, but doing the reaction at 50° C. for 20 h,1-(RS)-N-(2-methylprop-1-yl)amino-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopentane(lower R_(f) isomer from Steps A-D) (0.375 mg) was converted to thelower R_(f) title compound (0.435 g).

[1396] Step F:N-(2-Methylprop-1-yl)-N-(1-(SR)-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Higher R_(f) isomer) andN-(2-methylprop-1-yl)-N-(1-(RS)-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Lower R_(f) isomer)

[1397] A solution ofN-(2-methylprop-1-yl)-N-(1-(SR)-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Higher R_(f) isomer from Steps A-E) (270 mg, 0.57 mmol) and 1M TBAF inTHF (0.85 mL, 0.85 mmol) in THF (5 mL) was stirred at rt for 1 h. Thereaction was concentrated and the residue was purified by FC (20% ethylacetate in hexanes) to give the title higher R_(f) product (140 mg).

[1398] In a similar way,N-(2-methylprop-1-yl)-N-(1-(RS)-3-(SR)-t-butyldimethylsilyloxymethyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Lower R_(f) isomer from Steps A-E) (0.435 mg) was converted to thelower R_(f) title compound (0.300 mg).

[1399] Step G:N-(2-Methylprop-1-yl)-N-(1-(SR)-3-(SR)-formyl-4-(SR)-phenylcyclopent-1-yl)-glycine-(HigherR_(f) isomer) andN-(2-methylprop-1-yl)-N-(1-(RS)-3-(SR)-formyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Lower R_(f) Isomer)

[1400] Using essentially the same procedure as in Example 1, Step C,N-(2-methylprop-1-yl)-N-(1-(SR)-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Higher R_(f) isomer from Steps A-F) (140 mg, 0.39 mmol) was oxidized tothe title compound (100 mg).

[1401] In a similar way,N-(2-methylprop-1-yl)-N-(1-(RS)-3-(SR)-hydroxymethyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Lower R_(f) isomer from Steps A-F) (0.150 mg) was converted to thelower R_(f) title compound (0.140 mg).

[1402] Step H:N-(2-Methylprop-1-yl)-N-(1-(SR)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)glycinet-butyl Ester (Higher R_(f) Isomer)

[1403] To a solution ofN-(2-methylprop-1-yl)-N-(1-(SR)-3-(SR)-formyl-4-(SR)-phenylcyclopent-1-yl)-glycine(Higher R_(f) isomer from Steps A-G) (25 mg, 0.070 mmol) in1,2-dichloroethane (2 mL) was added 4-(3-(phenyl)prop-1-yl)piperidine(22 mg, 0.11 mmol) and acetic acid (0.006 mL, 0.11 mmol). After 15 min,sodium triacetoxyborohydride (45 mg, 0.21 mmol) was added and thereaction was stirred at rt for 4 h. The reaction was diluted withmethylene chloride, quenched with aq. sodium carbonate and extracted 3times with methylene chloride. The organic layers were each washed withbrine, dried over sodium sulfate, combined and concentrated in vacuo.The residue was purified by Prep TLC eluting with 5% methanol inmethylene chloride to give the title product (38 mg) as the free amine.

[1404] Step I:N-(2-Methylprop-1-yl)-N-(1-(SR)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)glycinedi-TFA salt A solution ofN-(2-methylprop-1-yl)-N-(1-(SR)-3-(SR)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)glycinet-butyl ester (higher R_(f) isomer from Steps A-H) (33 mg) in TFA (4 mL)was heated at 50° C. for 4 h and then the volatiles were removed under astream of nitrogen. An additional 2×3 mL of methylene chloride wereevaporated to dryness to afford the title compound as the di-TFA salt(50 mg).

[1405] HPLC/MS (ESI): m/z 491 (M+1).

EXAMPLE 41

[1406]N-(2-Methylprop-1-yl)-N-(1-(SR)-3-(SR)-((4-(3-(4-cyanophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)glycinedi-TFA Salt

[1407] Using essentially the same procedure as in Example 40, Steps Hand I, but substituting 4-(3-(4-cyanophenyl)prop-1-yl)piperidine (fromProcedure 7) in Step H, the title compound was prepared.

[1408] HPLC/MS (ESI): m/z 516 (M+1).

EXAMPLE 42

[1409]N-(2-Methylprop-1-yl)-N-(1-(SR)-3-(SR)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)glycinedi-TFA Salt

[1410] Using essentially the same procedure as in Example 40, Steps Hand I, but substituting 4-(3-(4-fluorophenyl)prop-1-yl)piperidine (fromProcedure 9) in Step H, the title compound can be prepared.

EXAMPLE 43

[1411]N-(2-Methylprop-1-yl)-N-(1-(RS)-3-(SR)-((4-(3-(4-cyanophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)glycinedi-TFA Salt

[1412] Using essentially the same procedure as in Example 40, Steps Hand I, but substituting the lower R_(f) aldehyde from Steps A-G and4-(3-(4-cyanophenyl)prop-1-yl)piperidine (from Procedure 7) in Step H,the title compound was prepared.

[1413] HPLC/MS (ESI): m/z 594 (M+1).

EXAMPLE 44

[1414]N-(2-Methylprop-1-yl)-N-(1-(RS)-3-(SR)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)glycinedi-TFA Salt

[1415] Using essentially the same procedure as in Example 40, Steps Hand I, but substituting the lower R_(f) aldehyde from Steps A-G and4-(3-(4-fluorophenyl)prop-1-yl)piperidine (from Procedure 9) in Step H,the title compound can be prepared.

EXAMPLE 45

[1416]N-(2-Methylprop-1-yl)-N-(1-(RS)-3-(SR)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopent-1-yl)-glycinedi-TFA Salt

[1417] Using essentially the same procedure as in Example 40, Steps Hand I, but substituting the lower R_(f) aldehyde from Steps A-G and4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidine (from Procedure 1) inStep H, the title compound can be prepared.

EXAMPLE 46

[1418]N-(Cyclobutylmethyl)-N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1419] Step A:N-(1-(R)-3-(S)-(Hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine andN-(1-(S)-3-(S)-Hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine

[1420] To a solution of(+)-trans-3-hydroxymethyl-4-phenylcyclopentan-1-one from Example 8, StepF, Method B (180 mg, 0.96 mmol), glycine t-butyl ester hydrochloride(241 mg, 1.44 mmol) and DIPEA (0.25 mL, 1.44 mmol) in 1,2-dichloroethane(6 mL) was added sodium triacetoxyborohydride (284 mg, 1.92 mmol). Thereaction was stirred at rt for 16 h and was then diluted with aq. sodiumbicarbonate and extracted three times with methylene chloride. Theorganic layers were each washed with brine, dried over sodium sulfate,combined and concentrated in vacuo. The residue was purified by FC(50-100% ethyl acetate in hexanes) to give the title product (196 mg) asa 2:1 mixture of C-1 free amine isomers.

[1421]¹H NMR (CDCl₃): δ 1.48 (s, 9H), 1.6-1.7 (m, 1.3H), 1.8-2.0 (2 m,1.7H), 2.23 (ddd. 0.3H), 2.3-2.45 (m, 2H), 2.68 (ddd, 0.7H), 3.2-3.4 (2m and 2 s, 3H), 3.45-3.65 (dABq (major) and d (minor), 2H), 3.96 (d,1H), 7.2-7.35 (m, 5H).

[1422] Step B:N-(Cyclobutylmethyl)-N-(1-(R)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine(Major, Higher R_(f)) andN-(cyclobutylmethyl)-N-(1-(S)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine(Minor, Lower R_(f))

[1423] To a solution of N-(1-(R andS)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine from Step A(180 mg, 0.59 mmol), cyclobutylaldehyde (27 mg, 0.32 mmol) and DIPEA(0.25 mL, 1.5 mmol) in 1,2-dichloroethane (6 mL) was added sodiumtriacetoxyborohydride (175 mg, 1.2 mmol). The reaction was stirred at rtfor 16 h and was then diluted with aq. sodium bicarbonate and extractedthree times with methylene chloride. The organic layers were each washedwith brine, dried over sodium sulfate, combined and concentrated invacuo. The residue was purified by Prep TLC (30% ethyl acetate inhexanes) to give the title 1-(R) product (45 mg pure, 31 mg mixture withthe 1-(S) diastereomer) as the higher R_(f) C-1 isomer. (Major, higherisomer): ¹H NMR (CDCl₃): δ 1.49 (s, 9H), 1.6-1.85 (m, 4H), 1.85-1.95 (m,2H), 2.0-2.15 (m, 2H), 2.24 (p, 1H), 2.2.33 (m, 1H), 2.53 (hept, 1H),2.7-2.8 (m, 3H), 3.31 (s, 2H), 3.4-3.5 (m, 1H), 3.48 and 3.61 (dABq,2H), 7.24 (tt, 1H), 7.25-7.35 (m, 4H).

[1424] Repurification of the mixture on Prep TLC afforded a sample ofpure 1-(S) minor, lower R_(f) isomer.

[1425] (Minor, lower isomer): ¹H NMR (CDCl₃): δ 1.47 (s, 9H), 1.6-1.75(m, 3H), 1.75-1.85 (m, 1H), 1.9-2.0 (m, 1H), 2.05-2.25 (m, 4H), 2.3 (m,1H), 2.54 (hept, 1H), 2.78 (ddd, 2H), 3.09 (q, 1H), 3.35 (ABq, 2H), 3.55(m, 1H), 3.61 (dABq, 2H), 7.24 (tt, 1H), 7.25-7.35 (m, 4H).

[1426] Step C:N-(Cyclobutylmethyl)-N-(1-(R)-3-(S)-(formyl)-4-(S)-phenylcyclopent-1-yl)glycine

[1427] Using essentially the same procedure as in Example 1, Step F,N-(cyclobutylmethyl)-N-(1-(R)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine(higher R_(f) isomer from Steps B) (45 mg, 0.12 mmol) was oxidized tothe title compound (56 mg crude without purification).

[1428] Step D:N-(Cyclobutylmethyl)-N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinet-butyl Ester

[1429] To a solution ofN-(cyclobutylmethyl)-N-(1-(R)-3-(S)-(formyl)-4-(S)-phenylcyclopent-1-yl)glycine(higher R_(f) isomer from Steps B-C) (22 mg, 0.059 mmol) in1,2-dichloroethane (1 mL) was added4-(3-(4-fluorophenyl)prop-1-yl)piperidine hydrochloride (from Procedure9) (23 mg, 0.089 mmol) and DIPEA (0.016 mL, 0.089 mmol). After 15 min,sodium triacetoxyborohydride (18 mg, 0.12 mmol) was added and thereaction was stirred at rt for 16 h. The reaction was diluted withmethylene chloride, quenched with aq. sodium carbonate and extracted 3times with methylene chloride. The organic layers were each washed withbrine, dried over sodium sulfate, combined and concentrated in vacuo.The residue was purified by Prep TLC eluting with 30% ethyl acetate inhexanes to give the title product (26 mg) as the free amine.

[1430] Step E:N-(Cyclobutylmethyl)-N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1431] A solution ofN-(cyclobutylmethyl)-N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinet-butyl ester (higher R_(f) isomer from Steps B-D) in TFA (4 ML) wasstirred at rt for 16 h and then the volatiles were removed under astream of nitrogen. An additional 2×3 mL of toluene were evaporated andthe residue was purified by Prep TLC (95:5:1:1 methylenechloride:methanol:water:NH₄OH). The free amine (5 mg) was taken up inmethylene chloride and excess 1M hydrogen chloride in ether was added.The mixture was evaporated to dryness to afford the title compound asthe di-HCl salt (7.3

[1432] HPLC/MS (ESI): m/z 521 (M+1).

EXAMPLE 47

[1433]N-(Cyclopropylmethyl)-N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1434] Using essentially the same procedure as in Example 46, Steps B-E,but substituting cyclopropylaldehyde in Step B, the title compound wasprepared.

[1435] HPLC/MS (ESI): m/z 507 (M+1).

EXAMPLE 48

[1436]N-(Cyclohexyl)-N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1437] Using essentially the same procedure as in Example 46, Steps B-E,but substituting cyclohexanone in Step B, the title compound wasprepared.

[1438] HPLC/MS (ESI): m/z 535 (M+1).

EXAMPLE 49

[1439]N-(Cyclopentylmethyl)-N-(1-(R)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1440] Using essentially the same procedure as in Example 46, Steps B-E,but substituting cyclopentylaldehyde in Step B, the title compound wasprepared.

[1441] HPLC/MS (ESI): m/z 535 (M+1).

EXAMPLE 50

[1442]N-(Cyclobutylmethyl)-N-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1443] Using essentially the same procedure as in Example 46, Steps B-E,but substituting the lower R_(f) product from Step B in Steps C-E, thetitle compound could be prepared.

[1444] HPLC/MS (ESI): m/z 521 (M+1).

EXAMPLE 51

[1445]N-(Cyclohexyl)-N-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1446] Using essentially the same procedure as in Example 46, Steps B-E,but substituting cyclohexanone in Step B and using the lower R_(f)product from Step B in Steps C-E, the title compound was prepared.

[1447] HPLC/MS (ESI): m/z 535 (M+1).

EXAMPLE 52

[1448]N-(Cyclopropylmethyl)-N-(-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1449] Using essentially the same procedure as in Example 46, Steps B-E,but substituting cyclopropyl aldehyde in Step B and using the lowerR_(f) product from Step B in Steps C-E, the title compound was prepared.

[1450] HPLC/MS (ESI): m/z 507 (M+1).

EXAMPLE 53

[1451] N-(Cyclopentylmethyl)-N-(1-(S)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1452] Using essentially the same procedure as in Example 46, Steps B-E,but substituting cyclopentyl aldehyde in Step B and using the lowerR_(f) product from Step B in Steps C-E, the title compound was prepared.

[1453] HPLC/MS (ESI): m/z 507 (M+1).

EXAMPLE 54

[1454]N-(Cyclohexyl)-N-(1-(S)-3-(S)-((4-(3-(3,4-difluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1455] Step A:N-(1-(S)-3-(S)-(t-Butyldimethylsilyloxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine(major, higher R_(f)) andN-(1-(R)-3-(S)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine(minor, lower R_(f))

[1456] To a solution of(+)-trans-3-t-butyldimethylsilyloxymethyl-4-phenylcyclopentan-1-one fromExample 16, Step A, Method B (332 mg, 1.1 mmol), glycine t-butyl esterhydrochloride (275 mg, 1.64 mmol) and DIPEA (0.285 mL, 1.64 mmol) in1,2-dichloroethane (13 mL) was added sodium triacetoxyborohydride (323mg, 2.18 mmol). The reaction was stirred at rt for 16 h and was thendiluted with aq. sodium bicarbonate and extracted three times withmethylene chloride. The organic layers were each washed with brine,dried over sodium sulfate, combined and concentrated in vacuo. Theresidue was purified by FC (10% ethyl acetate in hexanes) to give thetitle product (437 mg) as a 2.6:1 mixture of C-1 free amine isomers.(Note: The product C-1 isomer ratio here with the silyl ether isopposite to that of example 46 with the free alcohol. Also, note thatthe relative retention on TLC of the NH intermediates are opposite thatof the N-alkylation products of Step B.) Careful FC (5% ethyl acetate inhexanes) of an initial sample afforded the separated isomers.

[1457] (Major, higher isomer): ¹H NMR (CDCl₃): δ −0.05 (s, 3H), −0.04(s, 3H), 0.87 (s, 9 H), 1.42 (m, 1H), 1.50 (s, 9H), 1.98 (dd, 2H), 2.17(m, 1H), 2.27 (dt, 1H), 3.00 (q, 1H), 3.3-3.4 (m and s, 3H), 3.45 and3.60 (dABq, 2H), 7.15-7.25 (m, 3H), 7.25-7.35(m, 2H).

[1458] (Minor, lower isomer): ¹H NMR (CDCl₃): δ −0.05 (s, 3H), −0.04 (s,3H), 0.87 (s, 9 H), 1.50 (s, 9H), 1.62 (dt, 1H), 1.75 (ddd, 1H), 1.95(dt, 1H), 2.25-2.4 (2 m , 2H), 2.85 (m, 1H), 3.22 (m, 1H), 3.34 (s, 2H),3.42 and 3.54 (dABq, 2H), 7.24 (tt, 1H), 7.25-7.35 (m, 4H).

[1459] Step B:N-(Cyclohexyl)-N-(1-(S)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine(lower, major Rf) andN-(cyclohexyl)-N-(1-(R)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine(Higher, Minor R_(f))

[1460] To a solution of N-(1-(R andS)-3-(S)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylcyclopent-1-yl)glycinefrom Step A (437 mg, 1.04 mmol), cyclohexanone (0.650 mL, 6.24 mmol) andDIPEA (0.272 mL, 1.56 mmol) in 1,2-dichloroethane (10 mL) was addedsodium triacetoxyborohydride (693 mg, 0.68 mmol). The reaction wasstirred at rt for 16 h when additional cyclohexanone (0.600 mL) andsodium triacetoxyborohydride (300 mg) were added. After a further 48 h,the reaction was complete by HPLC/MS and was diluted with aq. sodiumbicarbonate and extracted three times with methylene chloride. Theorganic layers were each washed with brine, dried over sodium sulfate,combined and concentrated in vacuo. The residue (2 g) was used directlyin the following desilylation.

[1461] The residue from above was taken up in THF (10 mL) and 1M TBAF inTHF (5 mL, 5.0 mmol) was added. The reaction was stirred at rt for 6 hand was then poured into aq. sodium bicarbonate and extracted threetimes with ethyl acetate. The organic layers were each washed withbrine, dried over sodium sulfate, combined and concentrated in vacuo.The residue was purified by FC and Prep TLC (40% ethyl acetate inhexanes) to give the title (R) product (114 mg) as the minor, higherR_(f) band and the title (S) product (235 mg) as the major, lower R_(f)band.

[1462] (Major, higher isomer): ¹H NMR (CDCl₃): δ 1.1-1.4 (m, 5H), 1.48(s, 9H), 1.5-1.7 (m, 2H), 1.7-2.0 (m, 5H), 2.17 (m, 1H), 2.31 (m, 1H),2.65-2.8 (m, 2H), 3.24 (Abq, 2H), 3.45-3.55 (m, 2H), 3.6-3.7 (m, 2H),7.24 (tt, 1H), 7.25-7.35 (m, 4H).

[1463] (Minor, lower isomer): ¹H NMR (CDCl₃): δ 1.1-1.4 (m, 5H), 1.48(s, 9H), 1.6-1.7 (m, 2H), 1.7-2.0 (m, 5H), 2.17 (m, 2H), 2.25 (m, 1H),2.75 (m, 1H), 3.10 (q, 1H), 3.25 (Abq, 2H), 3.55-3.65 (m and ABq, 3H),7.24 (tt, 1H), 7.25-7.35 (m, 4H).

[1464] Step C:N-(Cyclohexyl)-N-(1-(S)-3-(S)-(formyl)-4-(S)-phenylcyclopent-1-yl)glycine

[1465] Using essentially the same procedure as in Example 1, Step C,N-(cyclohexyl)-N-(1-(S)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopent-1-yl)glycine(lower R_(f) isomer from Step B) (75 mg, 0.19 mmol) was oxidized to thetitle compound (84 mg crude without purification).

[1466] Step D:N-(Cyclohexyl)-N-(1-(R)-3-(S)-((4-(3-(3,4-difluorophenyl)prop-1-yl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinet-butyl Ester

[1467] To a solution ofN-(cyclohexyl)-N-(1-(S)-3-(S)-(formyl)-4-(S)-phenylcyclopent-1-yl)glycine(lower R_(f) isomer from Steps B-C) (19 mg, 0.050 mmol) in1,2-dichloroethane (1 mL) was added4-(3-(3,4-difluorophenyl)prop-1-yl)piperidine hydrochloride (fromProcedure 14) (15 mg, 0.054 mmol) and DIPEA (0.013 mL, 0.074 mmol).After 15 min, sodium triacetoxyborohydride (15 mg, 0.10 mmol) was addedand the reaction was stirred at rt for 16 h. The reaction was dilutedwith methylene chloride, quenched with aq. sodium carbonate andextracted 3 times with methylene chloride. The organic layers were eachwashed with brine, dried over sodium sulfate, combined and concentratedin vacuo. The residue was purified by Prep TLC eluting with 80% ethylacetate in hexanes to give the title product (20 mg) as the free amine.

[1468] Step E:N-(Cyclohexyl)-N-(1-(R)-3-(S)-((4-(3-(3,4-difluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1469] A solution ofN-(cyclohexyl)-N-(1-(R)-3-(S)-((4-(3-(3,4-difluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinet-butyl ester (lower R_(f) isomer from Steps B-D) (20 mg) in TFA (1 mL)was stirred at rt for 16 h and then the volatiles were removed under astream of nitrogen. The residue was taken up in methanol and adsorbedonto a 500 mg Varian SCX ion-exchange resin cartridge. The resin waseluted with 2×3 mL of methanol, then the product was eluted with 2×3 mLof 2M ammonia in methanol. The product solution was concentrated undernitrogen, then 2 volumes of methylene chloride were evaporated to removemethanol and ammonia to give the free amine. The hydrochloride salt wasprepared by dissolving the free amine in methylene chloride, addition ofexcess 1M hydrogen chloride in ether and evaporation to dryness.

[1470] HPLC/MS (ESI): m/z 553 (M+1).

EXAMPLE 55

[1471]N-(Cyclohexyl)-N-(1-(S)-3-(S)-((4-(3-(4-cyanophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1472] Using essentially the same procedure as in Example 54, Steps Dand E, but substituting 4-(3-(4-cyanophenyl)prop-1-yl)piperidine (fromProcedure 7) in Step D and using the lower R_(f) product from Step B inSteps C-E, the title compound was prepared.

[1473] HPLC/MS (ESI): m/z 542 (M+1).

EXAMPLE 56

[1474]N-(Cyclohexyl)-N-(1-(S)-3-(S)-((4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1475] Using essentially the same procedure as in Example 54, Steps Dand E, but substituting 4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidine(from Procedure 1) in Step D and using the lower R_(f) product from StepB in Steps C-E, the title compound was prepared.

[1476] HPLC/MS (ESI): m/z 583 (M+1).

EXAMPLE 57

[1477]N-(Cyclohexyl)-N-(1-(S)-3-(S)-((4-(N-propyl-N-(pyrrimidin-2-yl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1478] Using essentially the same procedure as in Example 54, Steps Dand E, but substituting 4-(N-propyl-N-(pyrrimidin-2-yl)amino)piperidine(from Procedure 13) in Step D and using the lower R_(f) product fromStep B in Steps C-E, the title compound was prepared.

[1479] HPLC/MS (ESI): m/z 534 (M+1).

EXAMPLE 58

[1480]N-(Cyclohexyl)-N-(1-(S)-3-(S)-((4-(3-(quinolin-3-yl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1481] Using essentially the same procedure as in Example 54, Steps Dand E, but substituting 4-(3-(quinolin-3-yl)prop-1-yl)amino)piperidine(from Procedure 10) in Step D and using the lower R_(f) product fromStep B in Steps C-E, the title compound was prepared.

[1482] HPLC/MS (ESI): m/z 568 (M+1).

EXAMPLE 59

[1483]N-(Cyclohexyl)-N-(1-(S)-3-(S)-((4-(4-fluorophenyl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)glycinedi-HCl Salt

[1484] Using essentially the same procedure as in Example 54, Steps Dand E, but substituting 4-(4-fluorophenyl)piperidine in Step D and usingthe lower R_(f) product from Step B in Steps C-E, the title compound wasprepared.

[1485] HPLC/MS (ESI): m/z 493 (M+1).

EXAMPLE 60

[1486]N-(1-(R)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-prolinedi-HCl Salt

[1487] Using essentially the same procedure as in Example 46, butsubstituting D-proline t-butyl ester in Step A, omitting Step B, andusing the higher R_(f) product from Step A in Steps C-E, the titlecompound was prepared.

[1488] HPLC/MS (ESI): m/z 493 (M+1).

EXAMPLE 61

[1489]N-(1-(S)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-prolinedi-HCl Salt

[1490] Using essentially the same procedure as in Example 46, butsubstituting D-proline t-butyl ester in Step A, omitting Step B, andusing the lower Rf product from Step A in Steps C-E, the title compoundwas prepared.

[1491] HPLC/MS (ESI): m/z 493 (M+1).

EXAMPLE 62

[1492]N-(1-(R)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-1-prolinedi-HCl Salt

[1493] Using essentially the same procedure as in Example 46, butsubstituting L-proline t-butyl ester in Step A, omitting Step B, andusing the higher Rf product from Step A in Steps C-E, the title compoundwas prepared.

[1494] HPLC/MS (ESI): m/z 493 (M+1).

EXAMPLE 63

[1495]N-(1-(S)-3-(S)-((4-(3-(4-Fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopent-1-yl)-D-prolinedi-HCl Salt

[1496] Using essentially the same procedure as in Example 46, butsubstituting L-proline t-butyl ester in Step A, omitting Step B, andusing the lower R_(f) product from Step A in Steps C-E, the titlecompound was prepared.

[1497] HPLC/MS (ESI): m/z 493 (M+1).

EXAMPLE 64

[1498]N-(1-(S)-3-(S)-((4-(3-Benzyl-1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-prolinedi-HCl Salt

[1499] Using essentially the same procedure as in Example 54, butsubstituting(+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentan-1-one fromexample 35, Step D and L-proline t-butyl ester in Step A, omitting StepB, using the lower R_(f) product from Step A in Steps C-E andsubstituting 4-(3-benzyl-1-ethyl-1H-pyrazol-5-yl)piperidine in Step F,the title compound was prepared.

[1500] HPLC/MS (ESI): m/z 559 (M+1).

EXAMPLE 65

[1501]N-Methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1502] Step A: Methyl(+−)-trans-4-methylene-2-(3-fluorophenyl)cyclopentanoate

[1503] A mixture of methyl trans-3-fluorocinnamate (4-1.25 g, 229 mmol),tetrakis(triphenylphosphine) palladium(O) (18.5 g, 16 mmol),1,2-bis(diphenylphosphino)ethane (5.5 g, 13.7 mmol) and2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (42.66 g, 229 mmol) inTHF (300 mL) under nitrogen was heated to reflux for 6 h and thenstirred at rt for 16 h. The reaction was diluted with hexane andfiltered to remove yellow precipitate. The volatiles were then removedin vacuo and the residue was purified by FC (3 to 5% ethyl acetate inhexanes) to afford the title compound (45 g).

[1504]¹H NMR (CDCl₃) δ: 2.52 (m, 1H), 2.68 (m, 1H), 2.8-2.9 (m, 2H),2.95 (ddd, 1H), 3.45 (ddd, 1H), 3.63 (s, 3H), 4.96 (m, 2H), 6.9-7.0 (m,2H), 7.03 (d, 1H), 7.2-7.3 (m, 1H).

[1505] Step B: (+−)-trans-4-Methylene-2-(3-fluorophenyl)cyclopentanoicAcid

[1506] To a solution of methyl(+−)-trans-4-methylene-2-(3-fluoro)phenylcyclopentanoate prepared as inStep A (47 g, 200 mmol) in methanol (500 mL) was added 5N sodiumhydroxide (200 mL, 1000 mmol). The reaction was stirred at rt for 60 hthen concentrated in vacuo. The residue was taken up in water, acidifiedwith 2M hydrochloric acid and extracted twice with methylene chloride.The organic layers were each washed with brine, dried over sodiumsulfate, combined and concentrated in vacuo to give the crude title acid(40.8 g) which was used directly in Step C.

[1507] (Note: The title compound can also be prepared in non-racemicform using essentially the same procedures as Example 8, Steps A-D usingthe chiral oxazolidine intermediate, [α]_(D)=+93 (MeOH, c=1).)

[1508] Step C:(+)-trans-1-Hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane and(−)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane

[1509] A solution of(+−)-trans-4-methylene-2-(3-fluorophenyl)cyclopentanoate (5.2 g, 23.6mmol) from Step B in THF (100 mL) was cooled to 0° C. under nitrogen and1M lithium aluminum hydride (LAH) in THF (35.4 mL) was added dropwiseover 10 min. The reaction was stirred at rt for 16 h, the excess LAH wasquenched by dropwise addition of acetone and the reaction was thenpoured into dilute aq. HCl. The mixture was extracted twice with etherand the organic layers were washed with brine, dried over sodiumsulfate, combined and concentrated. The residue was purified by FC (25%ethyl acetate in hexanes) to afford the racemic title product (4.1 g) asa an oil. Chiral Prep HPLC on a 2 cm×25 cm Chiracel OD column elutingwith 5% isopropanol in hexanes (25 injections) afforded the(−)-enantiomer, [α]_(D)=−45.5 (MeOH, c=0.9), as the first eluting peak(R_(t)=17.5 min) and the (+)-enantiomer (1.87 g), [α]_(D)=+45.0 (MeOH,c=1.0), as the second peak (R_(t)=22.0 min).

[1510]¹H NMR (CDCl₃) δ: 2.2-2.35 (m, 2H), 2.5 (m, 1H), 2.65-2.85 (m,2H), 2.9 (m, 1H), 3.51 and 3.68 (dABq, 2H), 4.93 (m, 2H), 6.9-7.0 (m,2H), 7.06 (d, 1H), 7.3-7.4 (m, 1H).

[1511] Step D:(+)-trans-3-Hydroxymethyl-4-(3-fluorophenyl)cyclopentanone

[1512] A solution of(+)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentanefrom Step C (1.87 g, 9.0 mmol) in methanol (75 mL) was cooled in a dryice/acetone bath and ozone was bubbled into the solution until the bluecolor persisted. The excess ozone was removed with a stream of nitrogenand then dimethylsulfide (5 mL) was added. After 10 min, the bath wasremoved and the reaction was allowed to warm to rt over 2 h. The mixturewas treated with 10 drops of sulfuric acid (c) in water (2 mL) for 1 hbefore most of the methanol was removed in vacuo. The mixture wasdiluted with water and extracted twice with ethyl acetate and theorganic layers were washed with brine, dried over sodium sulfate,combined and concentrated. The residue was purified by FC (50% ethylacetate in hexanes) to give the title compound (1.87 g), [α]_(D)=+132(MeOH, c=1.2).

[1513]¹H NMR (CDCl₃) δ: 2.3-2.45 (m, 2H), 2.5 (m, 1H), 2.61 and 2.77(dABq, 2H), 2.28 (ddd, 1H), 3.61 and 3.75 (dABq, 2H), 6.9-7.0 (m, 2H),7.06 (d, 1H), 7.3-7.4 (m, 1H).

[1514] (Note: The (+)-non-racemic title compound was also prepared byessentially the same reduction of non-racemic acid from Step B.)

[1515] Step E:N-(1-(R)-3-(S)-Hydroxymethyl-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl Ester

[1516] To a solution of(+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanone from Step D(1.0 g, 4.8 mmol) in 1,2-dichloroethane (50 ml) was added D-valinet-butyl ester (0.90 g, 5.2 mmol) and acetic acid (0.330 mL, 5.8 mmol).After 15 min, sodium triacetoxyborohydride (2.0 g, 5.6 mmol) was addedand the reaction was stirred at rt for 16 h. The reaction was dilutedwith methylene chloride, quenched with aq. sodium carbonate andextracted 3 times with methylene chloride. The organic layers were eachwashed with brine, dried over sodium sulfate, combined and concentratedin vacuo. The residue was purified by FC eluting with 30% ethyl acetatein hexanes to give the product (1.62 g) as a mixture of the higher R_(f)title compound and the C-1 isomer as the free amines.

[1517] Step F:N-Methyl-N-(1-(R)-3-(S)-hydroxymethyl-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl Ester

[1518] To a solution ofN-(1-(R)-3-(S)-hydroxymethyl-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl ester from Step E (1.62, 4.44 mmol) and 37 wt % formaldehyde inwater (2.1 mL, 27 mmol) in methanol (35 mL) was added 10% Pd/C (200 mg).After 10 min, the mixture was placed under hydrogen and stirred atatmospheric pressure for 60 h. The catalyst was removed by filtrationand the filtrate was evaporated. The residue was purified by FC elutingwith a gradient of 15 to 50% ethyl acetate in hexanes to give the higherR_(f) title product (1.44 g) and the lower C-I isomer (0.17 g) as thefree amines.

[1519] Step G:N-Methyl-N-(1-(R)-3-(S)-formyl-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl Ester

[1520] To a solution of oxalyl chloride (0.235 mL, 2.65 mmol) inmethylene chloride (10 mL) at −70° C. was added dropwise DMSO (0.385 mL,5.3 mmol). After 15 min, a solution ofN-methyl-N-(1-(R)-3-(S)-hydroxymethyl-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl ester (higher R_(f) isomer from Step F) (400 mg, 1.05 mmol) inmethylene chloride (10 mL) was added. The reaction was stirred at −70°C. for 1 h and then DIPEA (1.8 mL, 11 mmol) in methylene chloride (5 mL)was added dropwise over 5 min. After a further 10 min, the mixture wasallowed to warm to rt for 1 h and then diluted with methylene chloride.The layers were separated. The aq. layer was reextracted with a secondportion of methylene chloride and the organic layers were each washedwith brine, dried over sodium sulfate, combined and concentrated invacuo. The residue was purified by FC (15% ethyl acetate in hexanes) togive the title product (378 mg) as an oil.

[1521] Step H:N-Methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl Ester

[1522] To a solution ofN-methyl-N-(1-(R)-3-(S)-formyl-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl ester (250 mg, 0.66 mmol) from Step G in 1,2-dichloroethane (20mL) was added 4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride (from Procedure 1) (250 mg, 0.73 mmol) and DIPEA (0.25mL, 1.46 mmol). After 15 min, sodium triacetoxyborohydride (280 mg, 1.33mmol) was added and the reaction was stirred at rt for 16 h. Thereaction was diluted with methylene chloride, quenched with aq. sodiumcarbonate and extracted 3 times with methylene chloride. The organiclayers were each washed with brine, dried over sodium sulfate, combinedand concentrated in vacuo. The residue was purified by Prep TLC elutingwith 50% ethyl acetate in hexanes to give the title product as the freeamine.

[1523] HPLC/MS (ESI): m/z 631 (M+1).

[1524] Step I:N-Methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1525] TheN-methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl ester from Step H was taken up in TFA (2 mL) and aged at rt for16 h. The volatiles were evaporated under a stream of nitrogen. Theresidue was taken up in methanol and adsorbed onto a 500 mg Varian SCXion-exchange resin cartridge. The resin was eluted with 2×3 mL ofmethanol, then the product was eluted with 2×3 mL of 2M ammonia inmethanol. The product solution was concentrated under nitrogen, then 2volumes of methylene chloride were evaporated to remove methanol andammonia to give the free amine. The hydrochloride salt was prepared bydissolving the free amine in methylene chloride, adding excess (>3-fold)1M hydrogen chloride in ether and evaporating to dryness.

[1526] HPLC/MS (ESI): m/z 575 (M+1).

Carbon-13 and Proton Assignments Position Carbon-13 Proton(mult, \i J[Hz]) 1 64.0 3.46 2a 33.8 2.08 2b 1.83 — 3 42.8 2.33 4 49.6 2.69 5a 40.11.82 5b 2.22 — 6a 63.6 2.33 6b 2.19 — 7 73.5 3.11(d, J=7.3) 8 27.2 2.079 20.5 1.03(d, J=6.6) 10 19.3 0.90(d, J=6.7) 11 172.2 — 12 34.5 2.51(s)13 43.8 3.93(q, J=7.3) 14 16.1 1.26(t, J=7.3) 15 148.1 — 16 101.85.71(s) 17 151.3 — 18 35.1 3.79(s) 19 41.5 — 20 129.7 7.21 21 129.3 7.2522 126.9 7.16 2′ax 54.6 1.97 2′eq 2.76 — 3′ax 32.3 1.33(dq, J=3.9, 12.6)3′eq 1.59 — 4′ 33.2 2.48 5′ax 32.6 1.49(dq, J=4.0, 12.6) 5′eq 1.68 —6′ax 53.6 1.88 6′eq 2.92 — 1″ 148.1 — 2″ 115.2 7.05 (br d, J=10.8) 3″163.9 — 4″ 113.8 6.90(dt, J=2.5, 8.4) 5″ 130.9 7.27(m) 6″ 124.7 7.08(d,J=7.5)

EXAMPLE 66A

[1527]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-fluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1528] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(4-fluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1529] HPLC/MS (ESI): m/z 593 (M+1).

EXAMPLE 66B

[1530] N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3,4-difluorobenzyl)-1-methyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1531] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(3,4-difluorobenzyl)-1-methyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1532] HPLC/MS (ESI): m/z 597 (M+1).

EXAMPLE 66C

[1533]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1534] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1535] HPLC/MS (ESI): m/z 547 (M+1).

EXAMPLE 66D

[1536] N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-fluorophenyl)sulfonyleth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinedi-hydrochloride Salt

[1537] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(2-(4-fluorophenyl)sulfonyleth-1-yl)piperidinehydrochloride in Step H, the title compound was prepared.

[1538] HPLC/MS (ESI): m/z 577 (M+1).

EXAMPLE 66E

[1539]N-Methyl-N-(1-(R)-3-(S)-((4-(2-benzylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1540] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(2-(benzyl)thiazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1541] HPLC/MS (ESI): m/z 564 (M+1).

EXAMPLE 66F

[1542]N-Methyl-N-(-(R)-3-(S)-((4-(2-benzyl-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1543] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(2-benzyl-4-methylthiazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1544] HPLC/MS (ESI): m/z 578 (M+1).

EXAMPLE 66G

[1545]N-Methyl-N-(1-(R)-3-(S)-((4-(2-benzyl-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1546] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(2-benzyl-4-ethylthiazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1547] HPLC/MS (ESI): m/z 592 (M+1).

EXAMPLE 66H

[1548]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1549] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(4-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1550] HPLC/MS (ESI): m/z 605 (M+1).

EXAMPLE 66I

[1551]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-trifluoromethylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1552] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(3-(4-trifluoromethylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidine di-hydrochloride in Step H,the title compound was prepared.

[1553] HPLC/MS (ESI): m/z 643 (M+1).

EXAMPLE 66J

[1554]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(pyridin-3-ylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTetra-Hydrochloride Salt

[1555] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(pyridin-3-ylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinetri-hydrochloride in Step H, the title compound was prepared.

[1556] HPLC/MS (ESI): m/z 576 (M+1).

EXAMPLE 66K

[1557]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(pyridin-3-ylmethyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTetra-Hydrochloride Salt

[1558] Using essentially the same procedures as in Example 6-5, Steps Hand I, but substituting4-(3-(pyridin-3-ylmethyl)-(1H)-pyrazol-5-yl)piperidine tri-hydrochloridein Step H, the title compound was prepared.

[1559] HPLC/MS (ESI): rn/z 548 (M+1).

EXAMPLE 66L

[1560]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-chlorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1561] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(4-chlorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1562] HPLC/MS (ESI): rn/z 609 (M+1), 611 (M+3).

EXAMPLE 66M

[1563]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-fluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1564] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(3-fluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1565] HPLC/MS (ESI): m/z 593 (M+1).

EXAMPLE 66N

[1566]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3,5-difluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1567] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(3,5-difluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1568] HPLC/MS (ESI): m/z 611 (M+1).

EXAMPLE 66O

[1569]N-Methyl-N-(1-(R)-3-(S)-((4-(3-benzylpyridin-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valine Tri-Hydrochloride Salt

[1570] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(3-benzylpyridin-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1571] HPLC/MS (ESI): m/z 558 (M+1).

EXAMPLE 66P

[1572]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-cyanobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1573] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(4-cyanobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1574] HPLC/MS (ESI): m/z 600 (M+1).

EXAMPLE 66Q

[1575]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(cyclohexylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1576] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(cyclohexylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1577] HPLC/MS (ESI): m/z 581 (M+1).

EXAMPLE 66R

[1578]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1579] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(4-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1580] HPLC/MS (ESI): m/z 619 (M+1).

EXAMPLE 66S

[1581] N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-trifluoromethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1582] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(3-(4-trifluoromethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidine di-hydrochloride in Step H, the titlecompound was prepared.

[1583] HPLC/MS (ESI): m/z 659 (M+1).

EXAMPLE 66T

[1584] N-Methyl-N-(1-(R)-3-(S)-((4-((4-benzyl)-2-ethyl-(1H)-imidazol-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1585] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-((4-benzyl)-2-ethyl-(1H)-imidazol-1-yl))piperidine di-hydrochloride inStep H, the title compound was prepared.

[1586] HPLC/MS (ESI): m/z 575 (M+1).

EXAMPLE 66U

[1587]N-Methyl-N-(1-(R)-3-(S)-((4-((3-benzyl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1588] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-((3-benzyl)-1,2,4-oxadiazol-1-yl))piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1589] HPLC/MS (ESI): m/z 549 (M+1).

EXAMPLE 66V

[1590]N-Methyl-N-(1-(R)-3-(S)-((4-((2-benzyl)-4-ethyl-oxazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valine Tri-Hydrochloride Salt

[1591] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-((2-benzyl)4-ethyl-oxazol-5-yl))piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1592] HPLC/MS (ESI): m/z 576 (M+1).

EXAMPLE 66W

[1593]N-Methyl-N-(1-(R)-3-(S)-((4-(imidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1594] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(imidazo[1,2-A]pyridin-3-yl))piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1595] HPLC/MS (ESI): m/z 507 (M+1).

EXAMPLE 66X

[1596]N-Methyl-N-(1-(R)-3-(S)-((4-(6-trifluoromethylimidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1597] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(6-trifluoromethylimidazo[1,2-A]pyridin-3-yl))piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1598] HPLC/MS (ESI): m/z 575 (M+1).

EXAMPLE 66Y

[1599]N-Methyl-N-(1-(R)-3-(S)-((4-(6-ethylimidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1600] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting 4-(6-ethylimidazo[ l,2-A]pyridin-3-yl))piperidine di-hydrochloride in Step H, the titlecompound was prepared.

[1601] HPLC/MS (ESI): m/z 535 (M+1).

EXAMPLE 66Z

[1602] N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-methylsulfonylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1603] Using essentially the same procedures as in Example 65, Steps Hand I, but substituting4-(3-(4-methylsulfonylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1604] HPLC/MS (ESI): m/z 653 (M+1).

EXAMPLE 66AA

[1605]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-methylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1606] HPLC/MS (ESI): m/z 589.4 (M+1), R_(t)=1.62 min.

EXAMPLE 66BB

[1607]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-ethylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1608] HPLC/MS (ESI): m/z 603.5 (M+1), R_(t)=1.68 min.

EXAMPLE 66CC

[1609]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-isopropylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1610] HPLC/MS (ESI): m/z 617.4 (M+1), R_(t)=1.82 min.

EXAMPLE 66DD

[1611]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-t-butylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1612] HPLC/MS (ESI): m/z 631.7 (M+1), R_(t)=1.93 min.

EXAMPLE 66EE

[1613]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1614] HPLC/MS (ESI): m/z 605.7 (M+1), R_(t)=1.51 min.

EXAMPLE 66FF

[1615]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-difluoromethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1616] HPLC/MS (ESI): m/z 641.5 (M+1), R_(t)=1.68 min.

EXAMPLE 66GG

[1617]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-isopropoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1618] HPLC/MS (ESI): m/z 633.4 (M+1), R_(t)=1.66 min.

EXAMPLE 66HH

[1619]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3,4-methylenedioxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1620] HPLC/MS (ESI): m/z 619.5 (M+1), R_(t)=1.51 min.

EXAMPLE 66II

[1621] N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3,4-dimethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1622] HPLC/MS (ESI): m/z 635.5 (M+1), R_(t)=1.46 min.

EXAMPLE 66JJ

[1623] N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1624] HPLC/MS (ESI): m/z 619.6 (M+1), R_(t)=1.60 min.

EXAMPLE 66KK

[1625]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(2-naphthyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1626] HPLC/MS (ESI): m/z 625.6 (M+1), R_(t)=1.75 min.

EXAMPLE 66LL

[1627]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(1-naphthyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1628] HPLC/MS (ESI): m/z 625.6 (M+1), R_(t)=1.71 min.

EXAMPLE 66MM

[1629]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-fluoro-4-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1630] HPLC/MS (ESI): m/z 623.7 (M+1), R_(t)=1.58 min.

EXAMPLE 66NN

[1631]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-fluoro-4-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1632] HPLC/MS (ESI): m/z 637.6 (M+1), R_(t)=1.68 min.

EXAMPLE 66OO

[1633]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-cyano-4-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1634] HPLC/MS (ESI): m/z 630.7 (M+1), R_(t)=1.53 min.

EXAMPLE 66PP

[1635]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-cyclobutoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1636] HPLC/MS (ESI): m/z 645.5 (M+1), R_(t)=1.79 min.

EXAMPLE 66QQ

[1637]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzofuran-6-ylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1638] HPLC/MS (ESI): m/z 615.5 (M+1), R_(t)=1.55 min.

EXAMPLE 66RR

[1639]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(2,3-dihydrobenzofuran-6-ylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1640] HPLC/MS (ESI): m/z 617.5 (M+1), R_(t)=1.47 min.

EXAMPLE 66SS

[1641]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-benzyloxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1642] HPLC/MS (ESI): m/z 681.5 (M+1), R_(t)=1.64 min.

EXAMPLE 66TT

[1643]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-hydroxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1644] HPLC/MS (ESI): m/z 591.6 (M+1), R_(t)=1.29 min.

EXAMPLE 66UU

[1645]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-ethoxybenzyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1646] HPLC/MS (ESI): m/z 591.6 (M+1), R_(t)=1.53 min.

EXAMPLE 66VV

[1647]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-ethoxybenzyl)-1-(2-fluoroeth-1-yl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1648] HPLC/MS (ESI): m/z 637 (M+1), R_(t)=1.60 min.

EXAMPLE 66WW

[1649]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-cyclopropoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1650] HPLC/MS (ESI): m/z 631 (M+1), R_(t)=1.62 min.

EXAMPLE 66XX

[1651]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-phenylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1652] HPLC/MS (ESI): m/z 651 (M+1), R_(t)=1.80 min.

EXAMPLE 66YY

[1653]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-(2,2,2-trifluoroeth-1-yloxy)benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1654] HPLC/MS (ESI): m/z 673 (M+), R_(t)=1.69 min.

EXAMPLE 66ZZ

[1655]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-acetylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1656] HPLC/MS (ESI): m/z 617.5 (M+1), R_(t)=1.44 min.

EXAMPLE 66AAA

[1657]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-(1-methyl-1-hydroxyeth-1-yl)benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1658] HPLC/MS (ESI): m/z 633.5 (M+1), R_(t)=1.97 min.

EXAMPLE 66BBB

[1659]N-Methyl-N-(1-(R)-3-(S)-((4-(2-ethyl-(2H)-4,5,6,7-tetrahydroindazol-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yi)-D-valineTri-Hydrochloride Salt

[1660] HPLC/MS (ESI): m/z 539.5 (M+1), R_(t)=1.22 min.

EXAMPLE 66CCC

[1661]N-Methyl-N-(1-(R)-³-(S)-((4-(3-(4-methylcyclohexylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1662] HPLC/MS (ESI): m/z 595.5 (M+1), R_(t)=1.77 min.

EXAMPLE 66DDD

[1663]N-Methyl-N-(1-(R)-³-(S)-((4-(3-(pyran-4-ylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1664] HPLC/MS (ESI): m/z 583.7 (M+1), R_(t)=1.25 min.

EXAMPLE 66EEE

[1665]N-Methyl-N-(1-(R)-³-(S)-((4-(3-(cycloheptylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1666] HPLC/MS (ESI): m/z 595.7 (M+1), R_(t)=1.68 min.

EXAMPLE 66FFF

[1667] N-Methyl-N-(1-(R)-3-(S)-((4-(3-((1,1-dioxothiopyran-4-yl)methyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1668] HPLC/MS (ESI): m/z 631.5 (M+1), R_(t)=1.33 min.

EXAMPLE 66GGG

[1669]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-fluorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1670] HPLC/MS (ESI): m/z 582 (M+1).

EXAMPLE 66HHH

[1671]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-fluorobenzyl)-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1672] HPLC/MS (ESI): m/z 596 (M+1).

EXAMPLE 66III

[1673]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-fluorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1674] HPLC/MS (ESI): m/z 610 (M+1).

EXAMPLE 66JJJ

[1675]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-chlorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1676] HPLC/MS (ESI): m/z 598, 600 (M+1, M+3).

EXAMPLE 66KKK

[1677]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-chlorobenzyl)-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1678] HPLC/MS (ESI): mt/z 612, 614 (M+1, M+1).

EXAMPLE 66LLL

[1679]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-chlorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1680] HPLC/MS (ESI): m/z 626, 628 (M+1, M+1).

EXAMPLE 66MMM

[1681]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-trifluoromethylbenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochoride Salt

[1682] HPLC/MS (ESI): m/z 632 (M+1).

EXAMPLE 66NNN

[1683]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-trifluoromethylbenzyl)-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1684] HPLC/MS (ESI): m/z 646 (M+1).

EXAMPLE 66OOO

[1685]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-trifluoromethylbenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1686] HPLC/MS (ESI): m/z 660 (M+1).

EXAMPLE 66PPP

[1687]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2,4-difluorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1688] HPLC/MS (ESI): mlz 600 (M+1).

EXAMPLE-660QQQ

[1689]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2,4-difluorobenzyl)-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1690] HPLC/MS (ESI): m/z 614 (M+1).

EXAMPLE 66RRR

[1691]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2,4-difluorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1692] HPLC/MS (ESI): m/z 628 (M+1).

EXAMPLE 66SSS

[1693]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2,4-dichlorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1694] HPLC/MS (ESI): m/z 630,632,634 (M+1, M+3, M+5).

EXAMPLE 66TTT

[1695]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2,4-dichlorobenzyl)-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1696] HPLC/MS (ESI): m/z 644, 646, 648 (M+1, M+3, M+5).

EXAMPLE 66UUU

[1697] N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2,4-dichlorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1698] HPLC/MS (ESI): m/z 658, 660, 662 (M+1, M+3, M+5).

EXAMPLE 66VVV

[1699] N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-trifluoromethylbenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1700] HPLC/MS (ESI): m/z 632 (M+1).

EXAMPLE 66WWW

[1701]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-trifluoromethylbenzyl)-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1702] HPLC/IMS (ESI): m/z 646 (M+1).

EXAMPLE 66XXX

[1703]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-trifluoromethylbenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1704] HPLC/MS (ESI): m/z 660 (M+1).

EXAMPLE 66YYY

[1705]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,4-difluorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1706] HBLC/MS (ESI): m/z 600 (M+1).

EXAMPLE 66ZZZ

[1707]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,4-difluorobenzyl)-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1708] HPLC/MS (ESI): m/z 614 (M+1).

EXAMPLE 66AAAA

[1709]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,4-difluorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1710] HPLC/MS (ESI): m/z 628 (M+1).

EXAMPLE 66BBBB

[1711]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,4-dichlorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1712] HPLC/MS (ESI): m/z 630, 632, 634 (M+1, M+3, M+5).

EXAMPLE 66CCCC

[1713]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,4-dichlorobenzyl)-4-methylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1714] HPLC/MS (ESI): m/z 644, 646, 648 (M+1, M+3, M+5).

EXAMPLE 66DDDD

[1715]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,4-dichlorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1716] HPLC/MS (ESI): m/z 658, 660, 662 (M+1, M+3, M+5).

EXAMPLE 66EEEE

[1717]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,5-difluorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1718] HPLC/MS (ESI): m/l 600 (M+1).

EXAMPLE 66FFFF

[1719]N-Methyl-N-(1-(R)-3(S)-((4-(2-(3,5-difluorobenzyl)-4-methylthiazol-5-yl)piperidin-1-methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1720] HPLC/MS (ESI): m/z 614 (M+1).

EXAMPLE 66GGGG

[1721]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,5-difluorobenzyl)-4ethylthiazol-5yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1722] HPLC/MS (ESI): m/z 628 (M+1).

EXAMPLE 66HHHH

[1723]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(cyclohexylmethyl)thiazol-5-yl)pipeidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1724] HPLC/MS (ESI): m/z 570 (M+1).

EXAMPLE 66IIII

[1725]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(cyclohexylmethyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1726] HPLC/MS (ESI): m/z 598 (M+1).

EXAMPLE 66JJJJ

[1727]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2-chlorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride SSalt

[1728] HPLC/MS (ESI): m/z 598, 600 (M+1, M+3).

EXAMPLE 66KKKK

[1729]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2-chlorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1730] HPLC/MS (ESI): mlz 626, 628 (M+1, M+1).

EXAMPLE 66LLLL

[1731]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-chlorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1732] HPLC/MS (ESI): mlz 598, 600 (M+1, M+3).

EXAMPLE 66MMMM

[1733]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-chlorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1734] HPLC/MS (ESI): m/z 626,-628 (M+1, M+1).

EXAMPLE 66NNNN

[1735]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-fluorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1736] HPLC/MS (ESI): m/z 582 (M+1).

EXAMPLE 66OOOOOO

[1737]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-fluorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valine Tri-Hydrochloride Salt

[1738] HPLC/MS (ESI): m/z 610 (M+1).

EXAMPLE 66PPPP

[1739]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2-fluorobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochoride Salt

[1740] HPLC/MS (ESI): m/z 582 (M+1).

EXAMPLE 66OOOO

[1741]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2-fluorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1742] HPLC/MS (ESI): m/z 610 (M+1).

EXAMPLE 66RRRR

[1743]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2-trifluoromethylbenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1744] HPLC/MS (ESI): m/z 632 (M+1).

EXAMPLE 66SSSS

[1745]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2-trifluoromethylbenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1746] HPLC/MS (ESI): m/z 660 (M+1).

EXAMPLE 66TTTT

[1747]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-trifluoromethoxybenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1748] HPLC/MS (ESI): m/z 648 (M+1).

EXAMPLE 66UUUU

[1749]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-trifluoromethoxybenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1750] HPLC/MS (ESI): m/z 676 (M+1).

EXAMPLE 66VVVV

[1751]N-Methyl-N-(-(R)-3-(S)-((4-(2-(4-methylsulfonylbenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1752] HPLC/MS (ESI): m/z 642 (M+1).

EXAMPLE 66WWWW

[1753]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-methylsulfonylbenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1754] HPLC/MS (ESI): m/z 670 (M+1).

EXAMPLE 66XXXX

[1755] N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-nitrobenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1756] HPLC/MS (ESI): m/z 609 (M+1).

EXAMPLE 66YYYY

[1757]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-nitrobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1758] HPLC/MS (ESI): m/z 637 (M+1).

EXAMPLE 66ZZZZ

[1759]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-ethoxybenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1760] HPLC/MS (ESI): m/z 608 (M+1).

EXAMPLE 66AAAAA

[1761]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-ethoxybenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1762] HPLC/MS (ESI): m/z 636 (M+1).

EXAMPLE 66BBBBB

[1763]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-isopropylbenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1764] HPLC/MS (ESI): m/z 606 (M+1).

EXAMPLE 66CCCCC

[1765]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-isopropylbenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1766] HPLC/MS (ESI): m/z 634 (M+1).

EXAMPLE 66DDDDD

[1767]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-methoxybenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1768] HPLC/MS (ESI): m/z 594 (M+1).

EXAMPLE 66EEEEE

[1769]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-methoxybenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1770] HPLC/MS (ESI): m/z 622 (M+1).

EXAMPLE 66FFFFF

[1771] N-Methyl-N-(1-(R)-3-(S)-((4-(7-propylimidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1772] HPLC/MS (ESI): m/z 549 (M+1).

EXAMPLE 66GGGGG

[1773]N-Methyl-N-(1-(R)-3-(S)-((4-(7-t-butylimidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1774] HPLC/MS (ESI): m/z 563 (M+1).

EXAMPLE 66HHHHH

[1775]N-Methyl-N-(1-(R)-3-(S)-((4-(6-chloroimidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1776] HPLC/MS (ESI): m/z 541, 543 (M+1, M+3).

EXAMPLE 66IIIII

[1777]N-Methyl-N-(1-(R)-3-(S)-((4-(2-ethyl-5,6,7,8-tetrahydroimidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1778] HPLC/MS (ESI): m/z 539 (M+1).

EXAMPLE 66JJJJJ

[1779]N-Methyl-N-(1-(R)-3-(S)-((4-(6-fluoroimidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1780] HPLC/MS (ESI): m/z 525 (M+1).

EXAMPLE 66KKKKK

[1781] N-Methyl-N-(1 (R)-3-(S)-((4-(6-fluoro-7-methylimidazo[ 1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1782] HPLC/MS (ESI): m/z 539 (M+1).

EXAMPLE 66LLLLL

[1783]N-Methyl-N-(1-(R)-3-(S)-((4-(2-ethylimidazo[1,2-A]pyridin-3-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1784] HPLC/MS (ESI): m/z 535 (M+1).

EXAMPLE 66MMMMM

[1785]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2-thienyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1786] HPLC/MS (ESI): m/z 598 (M+1).

EXAMPLE 66NNNNN

[1787]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-thienyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride salt

[1788] HPLC/MS (ESI): m/z 598 (M+1).

EXAMPLE 66OOOOO

[1789]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-pyridyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1790] HPLC/MS (ESI): m/z 593 (M+1).

EXAMPLE 66PPPPP

[1791]N-Methyl-N-(1-(R)-3-(S)-((4-(2-benzyl-(2H)tetrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1792] HPLC/MS (ESI): m/z 549 (M+1).

EXAMPLE 66QQQQQ

[1793]N-Methyl-N-(1-(R)-3-(S)-((4-(1,3-diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1794] HPLC/MS (ESI): m/z 527 (M+1).

EXAMPLE 66RRRRR

[1795]N-Methyl-N-(1-(R)-3-(S)-((4-(1-ethyl-3,4-dimethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1796] HPLC/MS (ESI): m/z 513 (M+1).

EXAMPLE 66SSSSS

[1797]N-Methyl-N-(1-(R)-3-(S)-((4-(1,3-dimethyl-3-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1798] HPLC/MS (ESI): m/z 513 (M+1).

EXAMPLE 66TTTTT

[1799]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-trifluoromethysulfonylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1800] HPLC/MS (ESI): m/z 707 (M+1).

EXAMPLE 66UUUUU

[1801]N-Methyl-N-(1-(R)-3-(S)-((4-(1,3-dimethyl-3-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1802] HPLC/MS (ESI): m/z 513 (M+1).

EXAMPLE 67

[1803] N-Methyl-N-(1-(S)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1804] Using essentially the same procedures as in Example 65, Steps G,H and I, but substitutingN-methyl-N-(1-(S)-3-(S)-hydroxymethyl4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl ester (lower R_(f) isomer from Step F), the title compound wasprepared.

[1805] HPLC/MS (ESI): m/z 575 (M+1).

Example 67A

[1806]N-Methyl-N-(1-(S)-3-(S)-((4-(3-(3,4-difluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinetri-hydrochloride Salt

[1807] Using essentially the same procedures as in Example 67, butsubstituting4-(3-(3,4-difluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared. HPLC/MS(ESI): m/z 597 (M+1).

Example 67B

[1808]N-Methyl-N-(1-(S)-3-(S)-((4-(2-(4-fluorophenylsulfonyl)eth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1809] Using essentially the same procedures as in Example 67, butsubstituting 4-(3-(2-(4-fluorophenylsulfonyl)eth-1-yl)piperidinedi-hydrochloride in Step H, the title compound was prepared.

[1810] HPLC/MS (ESI): m/z 577 (M+1).

EXAMPLE 68

[1811]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-ethylglycinetri-hydrochloride Salt

[1812] Using essentially the same procedures as in Example 65, StepsE-I, but substituting (R)-ethylglycine-t-butyl ester in Step E and usingthe higher R_(f) isomer from Step F, the title compound was prepared.

[1813] HPLC/MS (ESI): m/z 561 (M+1).

EXAMPLE 69

[1814]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-norvalineTri-Hydrochloride Salt

[1815] Using essentially the same procedures as in Example 65, StepsE-I, but substituting D-norvaline-t-butyl ester in Step E and using thehigher R_(f) isomer from Step F, the title compound was prepared.

[1816] HPLC/MS (ESI): m/z 575 (M+1).

EXAMPLE 70

[1817]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1818] Using essentially the same procedures as in Example 65, StepsE-I, but substituting D-leucine-t-butyl ester in Step E and using thehigher R_(f) isomer-from Step F, the title compound was prepared.

[1819] HPLC/MS (ESI): m/z 589 (M+1).

EXAMPLE 71

[1820] Using essentially the same procedures as in Example 65, StepsE-I, but substituting D-leucine-t-butyl ester in Step E, using thehigher R_(f) isomer from Step F, and substituting the appropriatepiperidine in Step H, the following title compounds were prepared.

Example 71A

[1821]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-methylsulfonylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1822] HPLC/MS (ESI): m/z 667 (M+1).

Example 71B

[1823]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-trifluoromethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1824] HPLC/MS (ESI): m/z 673 (M+1).

Example 71C

[1825]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(cyclohexylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride SSalt

[1826] HPLC/MS (ESI): m/z 595 (M+1).

Example 71D

[1827]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(benzyl)-4-ethyl-thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1828] HPLC/MS (ESI): m/z 606 (M+1).

Example 71E

[1829]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-fluorobenzyl)-4-ethyl-thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1830] HPLC/MS (ESI): m/z 624 (M+1).

Example 71F

[1831]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-trifluoromethylbenzyl)-4-ethyl-thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1832] HPLC/MS (ESI): m/z 674 (M+1).

Example 71G

[1833]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(cyclohexylsulfonyl)eth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1834] HPLC/MS (ESI): m/z 579 (M+1).

Example 71H

[1835]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1836] HPLC/MS (ESI): m/z 619 (M+1).

Example 71I

[1837]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1838] HPLC/MS (ESI): m/z 619.4 (M+1), R_(t)=1.57 min.

Example 71J

[1839]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1840] HPLC/MS (ESI): m/z 633.6 (M+1).

Example 71K

[1841]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1842] HPLC/MS (ESI): m/z 633.7 (M+1), R_(t)=1.66 min.

EXAMPLE 71L

[1843]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-isopropoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1844] HPLC/MS (ESI): m/z 647.9 (M+1), R_(t)=1.69 min.

Example 71M

[1845]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-cyclopropoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1846] HPLC/MS (ESI): m/z 645.9 (M+1), R_(t)=1.66 min.

Example 71N

[1847]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-difluoromethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1848] HPLC/MS (ESI): m/z 655.4 (M+1), R_(t)=1.66 min.

Example 71O

[1849]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-cyclobutoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1850] HPLC/MS (ESI): mlz 659 (M+1), R_(t)=1.29 min.

EXAMPLE 71P

[1851]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-benzyloxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1852] HPLC/MS (ESI): m/z 695 (M+1), R_(t)=1.68 min.

Example 71Q

[1853]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-hydroxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1854] HPLC/MS (ESI): m/z 605 (M+1), R_(t)=1.35 min.

Example 71R

[1855]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-ethoxybenzyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1856] HPLC/MS (ESI): m/z 605.6 (M+1), R_(t)=1.57 min.

Example 71S

[1857]N-Methyl-N-(1-(R)-³-(S)-((4-(3-(4-(2,2,2-trifluoroethoxy)benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1858] HPLC/MS (ESI): m/z 687 (M+1), R_(t)=1.73 min.

EXAMPLE 71T

[1859]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3,4-methylenedioxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1860] HPLC/MS (ESI): m/z 633.8 (M+1), R_(t)=1.60 min.

EXAMPLE 71U

[1861]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3,4-dimethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1862] HPLC/MS (ESI): m/z 649.6 (M+1), R_(t)=1.47 min.

EXAMPLE 71V

[1863] N-Methyl-N-(1-(R)-³-(S)-((4-(3-(3-fluoro-4-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1864] HPLC/MS (ESI): m/z 637 (M+1), R_(t)=1.64 min.

Example 71W

[1865]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-fluoro-4-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1866] HPLC/MS (ESI): m/z 651 (M+1), R_(t)=1.75 min.

Example 71X

[1867]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3-cyano-4-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1868] HPLC/MS (ESI): n/z 644.7 (M+1), R_(t)=1.60 min.

Example 71Y

[1869]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzofuran-6-yl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1870] HPLC/MS (ESI): m/z 629 (M+1), R_(t)=1.60 min.

Example 71Z

[1871]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(2,3-dihydrobenzofuran-6-yl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1872] HPLC/MS (ESI): m/z 631 (M+1), R_(t)=1.53 min.

Example 71AA

[1873] N-Methyl-N-(l-(R)-3-(S)-((4-(3-(4-methylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1874] HPLC/MS (ESI): m/z 603.6 (M+1), R_(t)=1.68 min.

Example 71BB

[1875] N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-ethylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1876] HPLC/MS (ESI): m/z 617 (M+1), R_(t)=1.73 min.

Example 71CC

[1877]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-iospropylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1878] HPLC/MS (ESI): m/z 631.7 (M+1), R_(t)=1.90 min.

Example 71DD

[1879]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-t-butylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1880] HPLC/MS (ESI): mlz 645.7 (M+1), R_(t)=1.95 min.

Example 71EE

[1881]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(1-naphthyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1882] HPLC/MS (ESI): m/z 639.7 (M+1), R_(t)=1.77 min.

Example 71FF

[1883]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(2-naphthyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[1884] HPLC/MS (ESI): m/z 639.7 (M+1), R_(t)=1.86 min.

Example 71GG

[1885]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-phenylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1886] HPLC/MS (ESI): m/z 665 (M+1), R_(t)=1.84 min.

Example 71HH

[1887]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(pyran-4-ylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1888] HPLC/MS (ESI): m/z 597.7 (M+1), R_(t)=1.33 min.

Example 71II

[1889]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(cycloheptylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucinetri-hydrochloride Salt

[1890] HPLC/MS (ESI): m/z 609.7 (M+1), R_(t)=1.71 min.

EXAMPLE 72

[1891]N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycineTri-Hydrochloride Salt

[1892] Using essentially the same procedures as in Example 65, StepsE-I, but substituting (R)-t-butylglycine t-butyl ester in Step E,skipping Step F and using the higher R_(f) isomer from Step E, the titlecompound was prepared.

[1893] HPLC/MS (ESI): m/z 575 (M+1).

EXAMPLE 73

[1894] Using essentially the same procedures as in Example 72 andExample 65, Steps E-I, but substituting (R)-t-butylglycine t-butyl esterin Step E and skipping Step F, using the higher R_(f) isomer from Step E(as in Example 72), and substituting the appropriate piperidine in StepH, the following title compounds were prepared.

Example 73A

[1895]N-(1-(R)-3-(S)-((4-(3-(4-trifluoromethylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1896] HPLC/MS (ESI): m/z 643 (M+1).

Example 73B

[1897]N-(1-(R)-3-(S)-((4-(3-(4-fluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1898] HPLC/MS (ESI): m/z 593 (M+1).

Example 73C

[1899]N-(1-(R)-3-(S)-((4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycineTri-Hydrochloride Salt

[1900] HPLC/MS (ESI): m/z 547 (M+1).

Example 73D

[1901]N-(1-(R)-3-(S)-((4-(2-(benzyl)-4-ethyl-thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycineTri-Hydrochloride Salt

[1902] HPLC/MS (ESI): m/z 592 (M+1).

Example 73E

[1903]N-(1-(R)-3-(S)-((4-(3-(cyclohexylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1904] HPLC/MS (ESI): m/z 581 (M+1).

Example 73F

[1905]N-(1-(R)-3-(S)-((4-(3-(4-methylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1906] HPLC/MS (ESI): m/z 589 (M+1).

Example 73G

[1907]N-(1-(R)-3-(S)-((4-(3-(4-isopropylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1908] HPLC/MS (ESI): m/z 617 (M+1).

Example 73H

[1909]N-(1-(R)-3-(S)-((4-(3-(4-t-butylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1910] HPLC/MS (ESI): m/z 631 (M+1).

Example 73I

[1911]N-(1-(R)-3-(S)-((4-(3-(3-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1912] HPLC/MS (ESI): m/z 619 (M+1).

Example 73J

[1913]N-(1-(R)-3-(S)-((4-(3-(4-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1914] HPLC/MS (ESI): m/z 619 (M+1).

Example 73K

[1915]N-(1-(R)-³-(S)-((⁴-(3-(4-isopropyloxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1916] HPLC/MS (ESI): m/z 633 (M+1).

Example 73L

[1917]N-(1-(R)-3-(S)-((4-(3-(4-difluoromethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1918] HPLC/MS (ESI): m/z 641 (M+1).

Example 73M

[1919]N-(1-(R)-3-(S)-((4-(3-(2-naphthylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1920] HPLC/MS (ESI): m/z 625 (M+1).

EXAMPLE 74

[1921]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butyl-lycinetri-hydrochloride Salt

[1922] Using essentially the same procedures as in Example 65, StepsE-I, but substituting (R)-t-butylglycine t-butyl ester in Step E andusing the higher Rf isomer from Step F, the title compound was prepared.

[1923] HPLC/MS (ESI): m/z 589 (M+1).

EXAMPLE 75

[1924] Using essentially the same procedures as in Example 74 andExample 65, Steps E-I, but substituting (R)-t-butylglycine t-butyl esterin Step E, using the higher R_(f) isomer from Step F, and substitutingthe appropriate piperidine in Step H, the following title compounds wereprepared.

Example 75A

[1925]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-trifluoromethylbenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1926] HPLC/MS (ESI): m/z 657 (M+1).

Example 75B

[1927]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-fluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1928] HPLC/MS (ESI): m/z 607 (M+1).

Example 75C

[1929]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(3,4-difluorobenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1930] HPLC/MS (ESI): m/z 625 (M+1).

Example 75D

[1931]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-methoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1932] HPLC/MS (ESI): m/z 619 (M+1).

Example 75E

[1933]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(cyclohexylmethyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1934] HPLC/MS (ESI): m/z 595 (M+1).

Example 75F

[1935]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycineTri-Hydrochloride Salt

[1936] HPLC/MS (ESI): m/z 561 (M+1).

Example 75G

[1937]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(4-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-ylypiperidin-1-yi)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1938] HPLC/MS (ESI): n/z 633 (M+1).

Example 75H

[1939]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(benzyl)-4-ethyl-thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycineTri-Hydrochloride Salt

[1940] HPLC/MS (ESI): m/z 606 (M+1).

Example 75I

[1941]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-fluorobenzyl)-4-ethyl-thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1942] HPLC/MS (ESI): m/z 624 (M+1).

Example 75J

[1943]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-trifluoromethylbenzyl)thiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1944] HPLC/MS (ESI): m/z 646 (M+1).

Example 75K

[1945]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3-trifluoromethylbenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1946] HPLC/MS (ESI): m/z 674 (M+1).

Example 75L

[1947]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,4-dichlorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1948] HPLC/MS (ESI): m/z 673, 675, 677 (M+1, M+3, M+4).

Example 75M

[1949]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(4-chlorobenzyl)-4-ethyloxazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1950] HPLC/MS (ESI): m/z 624, 626 (M+1, M+3).

Example 75N

[1951]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(2,4-difluorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butyglycinetri-hydrochloride Salt

[1952] HPLC/MS (ESI): m/z 642 (M+1).

EXAMPLE 75O

[1953]N-Methyl-N-(1-(R)-3-(S)-((4-(2-(3,4-difluorobenzyl)-4-ethylthiazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-(R)-t-butylglycinetri-hydrochloride Salt

[1954] HPLC/MS (ESI): m/z 642 (M+1).

EXAMPLE 76

[1955]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(phenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[1956] Using essentially the same procedures as in Example 65, StepsA-I, but substituting methyl trans-cinnamate in Step A and using thehigher R_(f) isomer from Step F, the title compound was prepared.

[1957] HPLC/MS (ESI): m/z 557 (M+1).

EXAMPLE 77

[1958]N-Methyl-N-(1-(S)-3-(R)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(R)-(3-fluorophenyl)cyclopent-1-yl)-1-valineTri-Hydrochloride Salt

[1959] Using essentially the same procedures as in Example 65, StepsD-I, but substituting the faster (−)-enantiomer from Step C in Step D,L-valine in Step E and using the higher R_(f) isomer from Step F, thetitle compound was prepared.

[1960] HPLC/MS (ESI): m/z 575 (M+1).

EXAMPLE 78

[1961] N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylicAcid Tri-Hydrochloride Salt

[1962] Step A:3-(S)-(Benzyloxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane

[1963] To a solution of3-(S)-(hydroxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane(3.11 g, 16.5 mmol) from Example 65, Step C in DMF (100 mL) was addedbenzyl bromide (4.24 g, 24.8 mmol) and then sodium hydride (60% inmineral oil, 0.73 g, 18.2 mmol) portionwise over 5 min. The reaction wasstirred at rt for 16 h, then diluted with ether (100 mL) and quenchedslowly into aq. sodium bicarbonate (200 mL). The layers were separatedand the aqueous was extracted with ether. The organic layers were washed3× with water, then brine, dried over sodium sulfate and concentrated.The residue (7 g) was purified by FC using 0.5-1% ethyl acetate inhexanes to afford the title compound (2.32 g).

[1964] Step B:3-(S)-(Benzyloxymethyl)-4-(S)-(3-fluorophenyl)cyclopentanone

[1965] A solution of3-(S)-(benzyloxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane(0.77 g, 2.75 mmol) from Step A in methanol (30 mL) was cooled to −70°C. and ozone was bubbled through the solution until a blue colorpersisted. The excess ozone was removed with a stream of nitrogen andthen di methyl sulfide (5 mL) was added and the reaction was allowed towarm to rt over 16 h. Several drops of 2N HCl were added and thesolution was stirred for 15 min to convert any methyl ketal to thedesired ketone. The methanol was removed in vacuo and the was residuediluted with water, aq. sodium bicarbonate and ether. ). The layers wereseparated and the aqueous was extracted with ether. The organic layerswere washed with water, then brine, dried over sodium sulfate andconcentrated. The residue was purified by FC using 10% ethyl acetate inhexanes to afford the title compound (0.88 g).

[1966] Step C: t-Butyl N-(1-(R andS)-3-(S)-(benzyloxymethyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate

[1967] To a mixture of3-(S)-(benzyloxymethyl)-4-(R)-(3-fluorophenyl)cyclopentanone (365 mg,1.3 mmol) from Step B and t-butyl 1-aminocyclopentanecarboxylate (349mg, 1.8 mmol) was added 5 mL of titanium tetra-t-butoxide at rt. After 2h the reaction was diluted with methanol (2 mL) and sodium borohydride(48 mg, 1.3 mmol) was added. The reaction was stirred for 0.5 h, dilutedwith water, filtered and concentrated. The residue was taken up in waterand extracted twice with ethyl acetate. The organic layers were washedwith brine,-dried over sodium sulfate and concentrated. The residue waspurified by FC using 1% TEA in 20% ethyl acetate in hexanes to affordthe title compound (275 mg) as a mixture of C-1 isomers.

[1968] (Note: The reaction is faster using titanium tetra-isopropoxide,especially with more hindered amines, however, trans esterification tothe isopropyl ester can occur in the above reaction, especially withless hindered amines.)

[1969] Step D: t-Butyl N-methyl-N-(1-(R andS)-3-(S)-(benzyloxymethyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate

[1970] To a solution of t-butyl N-(1-(R andS)-3-(S)-(benzyloxymethyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate(635 mg, 1.4 mmol) from Step C in DCE (25 mL) was added acetic acid(0.117 mL 2.0 mmol), 37% aq. formaldehyde (0.22 mL, 2.7 mmol) and thensodium triacetoxyborohydride (576 mg, 2.7 mmol). After 1.5 h, thereaction was diluted with aq. sodium bicarbonate solution, extracted 3×with DCM, washed with brine, dried over sodium sulfate and concentrated.The residue was purified by FC using 15% ethyl acetate in hexanes toafford the title compound (678 mg) as a mixture of C-1 isomers).

[1971] Step E: t-Butyl N-methyl-N-(1-(R andS)-3-(S)-(hydroxymethyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate

[1972] A mixture of t-butyl N-(1-(R andS)-3-(S)-(benzyloxymethyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate(678 mg, 0.1.4 mmol) from Step D, acetic acid (0.080 mL, 0.1.4 mmol) and20% palladium hydroxide on carbon (200 mg) in methanol (6 mL) was shakenunder 50 psi hydrogen for 4 days. The reaction was filtered, washed withmethanol and concentrated. The residue was taken up in water andextracted 3x with DCM. The organic layers were washed with brine, driedover sodium sulfate and concentrated. The residue was purified by FCusing in 50-60% ethyl acetate in hexanes to afford separation of the C-1title compound isomers, higher R_(f) (145 mg) and lower R_(f) (275 mg).

[1973] Step F: t-ButylN-methyl-N-(1-(R)-3-(S)-(formyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate

[1974] Using essentially the same procedure as in Example 65, Step G,t-butylN-methyl-N-(1-(R)-3-(S)-(hydroxymethyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate(100 mg) from Step E (higher R_(f) product) was converted to the titlecompound (100 mg crude).

[1975] Step G: t-ButylN-methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate

[1976] Using essentially the same procedure as in Example 65, Step H,t-butylN-methyl-N-(1-(R)-3-(S)-(formyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate(50 mg) from Step F (derived from the higher R_(f) product from Step E)was converted to the title compound (113 mg).

[1977] Step H:N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylicAcid tri-hydrochloric Scid Salt

[1978] Using essentially the same procedure as in Example 65, Step I,t-butylN-methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentanecarboxylate(113 mg) from Step G (derived from the higher R_(f) product from Step E)was converted to the title compound (30 mg) as a single isomer. HPLC/MS(ESI): m/z 587.5 (M+1), R_(t)=1.51 min.

EXAMPLE 79

[1979]N-Methyl-N-(1-(S)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentaneCarboxylic Acid Tri-Hydrochloride Salt

[1980] Using essentially the same procedures as in Example 78, butsubstituting lower R_(f) isomer from Step E, the title compound wasprepared. HPLC/MS (ESI): m/z 587.5 (M+1), R_(t)=1.53 min.

EXAMPLE 80

[1981]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentaneCarboxylic Acid Tri-Hydrochloride Salt

[1982] Using essentially the same procedures as in Example 78, using thehigher R_(f) isomer from Step E, and substituting(4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidine in Step G, the titlecompound was prepared.

[1983] HPLC/MS (ESI): m/z 559.5 (M+1), R_(t)=1.46 min.

EXAMPLE 81

[1984]N-Methyl-N-(1-(S)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentaneCarboxylic Acid Tri-Hydrochloride Salt

[1985] Using essentially the same procedures as in Example 78, using thelower R_(f) isomer from Step E, and substituting(4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidine in Step G, the titlecompound was prepared.

[1986] HPLC/MS (ESI): m/z 559.5 (M+1), R_(t)=1.46 min.

EXAMPLE 82

[1987]N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentaneCarboxylic Acid Tri-Hydrochloride Salt

[1988] Using essentially the same procedures as in Example 78, skippingStep D, using the higher R_(f) isomer from Step E, the title compoundwas prepared. HPLC/MS (ESI): m/z 573.5 (M+1), R_(t)=1.58 min.

EXAMPLE 83

[1989]N-(1-(S)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentaneCarboxylic Acid Tri-Hydrochloride Salt

[1990] Using essentially the same procedures as in Example 78, skippingStep D, using the lower R_(f) isomer from Step E, the title compound wasprepared. HPLC/MS (ESI): m/z 573.5 (M+1), R_(t)=1.58 min.

EXAMPLE 84

[1991] N-(1-(S orR)-3-(R)-((4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentaneCarboxylic Acid Tri-Hydrochloride Salt

[1992] Using essentially the same procedures as in Example 78, skippingStep D, using the higher R_(f) isomer from Step E, and substituting(4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidine in Step G, the titlecompound was prepared.

[1993] HPLC/MS (ESI): m/z 545.5 (M+1), R_(t)=1.55 min.

EXAMPLE 85

[1994] N-(1-(R orS)-3-(S)-((4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-1-aminocyclopentaneCarboxylic Acid Tri-Hydrochloride Salt

[1995] Using essentially the same procedures as in Example 78, skippingStep D, using the lower R_(f) isomer from Step E, and substituting(4-(3-(benzyl)-(1H)-pyrazol-5-yl)piperidine in Step G, the titlecompound was prepared.

[1996] HPLC/MS (ESI): m/z 545.5 (M+1), R_(t)=1.64 min.

EXAMPLE 86

[1997]N-Methyl-N-(1-(R)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-α,α-dimethylglycineTri-Hydrochloride Salt

[1998] Using essentially the same procedures as in Example 78, butsubstituting α,α-dimethylglycine t-butyl ester in Step C and using thehigher Rf isomer from Step E, the title compound was prepared.

[1999] HPLC/MS (ESI): m/z 561.5 (M+1), R_(t)=1.46 min.

EXAMPLE 87

[2000]N-Methyl-N-(1-(S)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-α,α-dimethylglycineTri-Hydrochloride Salt

[2001] Using essentially the same procedures as in Example 78, butsubstituting α,α-dimethylglycine t-butyl ester in Step C and using thelower R_(f) isomer from Step E, the title compound was prepared.

[2002] HPLC/MS (ESI): m/z 561.5 (M+1), R_(t)=1.46 min.

EXAMPLE 88

[2003] N-Methyl-N-(1-(R andS)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-Dand L-α-methylleucine Tri-Hydrochloride Salt

[2004] Using essentially the same procedures as in Example 78, butsubstituting D/L-α-methylleucine t-butyl ester in Step C, all four ofthe title compound isomers were prepared.

[2005] HPLC/MS (ESI): m/z 589.5 (M+1), R_(t)=1.64 min.

[2006] HPLC/MS (ESI): m/z 589.6 (M+1), R_(t)=1.68 min.

[2007] HPLC/MS (ESI): m/z 589.5 (M+1), R_(t)=1.73 min.

[2008] HPLC/MS (ESI): m/z 589.5 (M+1), R_(t)=1.62 min.

EXAMPLE 89

[2009] N-(1-(R andS)-3-(S)-((4-(3-(benzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-Dand L-α-methylleucine Tri-Hydrochloride Salt

[2010] Using essentially the same procedures as in Example 78, butsubstituting D/L-α-methylleucine t-butyl ester in Step C and skippingStep D, all four of the title compound isomers were prepared as singlediastereomers at either Step D or E, but the stereochemical assignmentswere not made.

[2011] HPLC/MS (ESI): m/z 575.5 (M+1), R_(t)=1.52 min.

[2012] HPLC/MS (ESI): m/z 575.5 (M+1), R_(t)=1.53 min.

[2013] HPLC/MS (ESI): m/z 575.5 (M+1), R_(t)=1.55 min.

[2014] HPLC/MS (ESI): m/z 575.5 (M+1), R_(t)=1.58 min.

EXAMPLE 90

[2015]N-Isopropyl-N-(1-(R)-3-(S)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)glycineTri-Hydrochloride Salt

[2016] Using essentially the same procedures as in Example 46, butsubstituting acetone in Step B and using the higher isomer from Step B,the title compound was prepared.

[2017] HPLC/MS (ESI): m/z 495 (M+1).

EXAMPLE 91

[2018]N-Isopropyl-N-(1-(S)-3-(S)-((4-(3-(phenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)glycineTri-Hydrochloride Salt

[2019] Using essentially the same procedures as in Example 46, butsubstituting acetone in Step B and using the lower isomer from Step B,the title compound was prepared.

[2020] HPLC/MS (ESI): m/z 495 (M+1).

EXAMPLE 92

[2021]N-Methyl-N-(1-(R)-3-(S)-((4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2022] Step A:N-Methyl-N-(1-(R)-3-(S)-((4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineBenzyl Ester

[2023] The title compound was prepared using procedures analogous tothose described in EXAMPLE 65, Steps D-H, substituting D-valine benzylester for D-valine t-butyl ester in Step D and using4-(3,3-difluoro-3-(4-fluorophenyl)propyl)piperdine (from PROCEDURE 17)in Step H. For the title compound:

[2024] ESI-MS 653 (M+H); HPLC A: 1.98 min.

[2025] Step B:N-Methyl-N-(1-(R)-3-(S)-((4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2026]N-Methyl-N-(1-(R)-3-(S)-((4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valine(40 mg, 0.061 mmol) from EXAMPLE 92, Step A, in 95% ethanol (4.0 ml) washydrogenated at atmospheric pressure using 10% palladium on carbon (10mg). After 2 h, the mixture was filtered, the catalyst was washed with95% ethanol, and the filtrate was evaporated. The crude product waspurified by flash column chromatography on silica gel packed in CH₂Cl₂.Elution with 95:5:1 v/v/v CH₂Cl₂/CH₃OH/NH₄OH followed by 90:10:2 v/v/vCH₂Cl₂/CH₃OHNH₄OH gave 28 mg of the title compound:

[2027] ESI-MS 563 (M+H); HPLC A: 1.69 min.

EXAMPLE 93

[2028]N-Methyl-N-(1-(R)-3-(S)-((4-(3,3-difluoro-3-(6-methylpyridazin-3-yl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2029] The title compound was prepared using procedures analogous tothose described in EXAMPLE 92, using4-(3,3-difluoro-3-(6-methylpyridazin-3-yl)propyl)piperidine (fromPROCEDURE 36). For the title compound:

[2030] ESI-MS 561 (M+H); HPLC A: 1.30 min.

EXAMPLE 94

[2031]N-Methyl-N-(1-(R)-3-(S)-((4-(3,3-difluoro-3-(4-trifluoromethytl-2-pyridyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2032] The title compound was prepared using procedures analogous tothose described in EXAMPLE 92, using4-(3,3-difluoro-3-(5-(trifluoromethyl)pyrid-2-yl)propyl)piperidine (fromPROCEDURE 37). For the title compound:

[2033] ESI-MS 614 (M+H); HPLC A: 1.68 min.

EXAMPLE 95

[2034]N-Methyl-N-(1-(R)-3-(S)-((4-(3,3-difluoro-3-(2-pyridyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2035] The title compound was prepared using procedures analogous tothose described in EXAMPLE 92, using4-(3,3-difluoro-3-(3-pyridyl)propyl)piperidine (from PROCEDURE 38). Forthe title compound: ESI-MS 546 (M+H); HPLC A: 1.18 min.

EXAMPLE 96

[2036]N-Methyl-N-(1-(R)-3-(S)-((4-(3,3-difluoro-3-(1-methyl-pyrazol-4-yl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2037] The title compound was prepared using procedures analogous tothose described in EXAMPLE 92, using4-(3,3-difluoro-3-(1-methylpyrazol4-yl)propyl)piperidine (from PROCEDURE39). For the title compound:

[2038] ESI-MS 549 (M+H); HPLC A: 1.36 min.

EXAMPLE 97

[2039] Using essentially the same procedure as in Example 35, Steps E toH, but substituting the appropriate L- and/or D-aminoacid t-butyl esterin Step E and the appropriate piperidine in Step G, the followingcompounds A-F were prepared.

Example 97A

[2040]N-(1-(R)-3-(S)-((4-(2-(4-Fluorophenylsulfonyl)eth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclohexylglycineDi-Hydrochloride Salt

[2041] HPLC/MS (ESI): m/z 603 (M+1).

Example 97B

[2042]N-(1-(R)-3-(S)-((4-(2-(4-Fluorophenylsulfonyl)eth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-isoleucineDi-Hydrochloride Salt

[2043] HPLC/MS (ESI): m/z 577 (M+1).

Example 97C

[2044]N-(1-(R)-3-(S)-((4-(2-(4-Fluorophenylsulfonyl)eth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclobutylmethylglycineDi-Hydrochloride Salt

[2045] HPLC/MS (ESI): m/z 589 (M+1).

EXAMPLE 97D

[2046]N-(1-(R)-3-(S)-((4-(2-(4-Fluorophenylsulfonyl)eth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineDi-Hydrochloride Salt

[2047] HPLC/MS (ESI): m/z 563 (M+1).

Example 97E

[2048]N-(1-(R)-3-(S)-((4-(2-(4-Fluorophenylsulfonyl)eth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-alloleucineDi-Hydrochloride Salt

[2049] HPLC/MS (ESI): m/z 577 (M+1).

Example 97F

[2050]N-(1-(R)-3-(S)-((4-(2-(4-Fluorophenylsullfonyl)eth-1-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineDi-Hydrochloride Salt

[2051] HPLC/MS (ESI): m/z 577 (M+1).

EXAMPLE 98

[2052] Using essentially the same procedure as in Example 35, Steps E toH, but substituting the appropriate L- and/or D-aminoacid t-butyl esterin Step E, the following compounds A-E were prepared.

Example 98A

[2053]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-cyclobutylalanineTri-Hydrochloride Salt

[2054] HPLC/MS (ESI): m/z 587 (M+1).

Example 98B

[2055]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-alloleucineTri-Hydrochloride Salt

[2056] HPLC/MS (ESI): m/z 575 (M+1).

Example 98C

[2057]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-leucineTri-Hydrochloride Salt

[2058] HPLC/MS (ESI): m/z 575 (M+1).

Example 98D

[2059]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2060] HPLC/MS (ESI): m/z 561 (M+1).

Example 98E

[2061]N-(1-(R)-3-(S)-((4-(3-Benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-isoleucineTri-Hydrochloride Salt

[2062] HPLC/MS (ESI): m/z 575 (M+1).

EXAMPLE 99

[2063]N-Ethyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2064] Using essentially the same procedure as in Example 65, Steps F toH, but substituting acetaldehyde in Step F, the title compound wasprepared.

[2065] HPLC/MS (ESI): m/z 589 (M+1).

EXAMPLE 100

[2066]N-Ethyl-N-(1-(R)-3-(S)-((4-(3-(4-ethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2067] Using essentially the same procedure as in Example 65, Steps F toH, but substituting acetaldehyde in Step F, the title compound wasprepared.

[2068] HPLC/MS (ESI): m/z 633 (M+1).

EXAMPLE 101

[2069]N-Ethyl-N-(1-(R)-3-(S)-((4-(3-(3,4-dimethoxybenzyl)-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2070] Using essentially the same procedure as in Example 65, Steps F toH, but substituting acetaldehyde in Step F, the title compound wasprepared.

[2071] HPLC/MS (ESI): m/z 649 (M+1).

EXAMPLE 102

[2072]N-Ethyl-N-(1-(R)-3-(S)-((4-(1,3-diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2073] Using essentially the same procedure as in Example 65, Steps F toH, but substituting acetaldehyde in Step F, the title compound wasprepared.

[2074] HPLC/MS (ESI): m/z 541 (M+1).

EXAMPLE 103

[2075] N-Methyl-N-(1-(R)-3-(S)-(1-(R andS)-(4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)eth-1-yl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valineTri-Hydrochloride Salt

[2076] Using essentially the same procedures as Example 65, Step G-I,but substituting, N-methyl-N-(1-(R)-3-(S)-(1-(R andS)-hydroxyeth-1-yl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valinet-butyl ester (obtained by addition at 0° C. in THF for 1 h of methylmagnesium bromide to the aldehyde from Example 65, Step G), the titlecompounds were obtained as a mixture of isomers.

[2077] HPLC/MS (ESI): m/z 589 (M+1).

EXAMPLE 104

[2078] N-Methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valine

[2079] A 100-L flask equipped with mechanic stirrer, thermocouple,nitrogen inlet, and addition funnel was charged with nitrogen and thenwith toluene (60 L) and 3-fluorobenzaldehyde (1, 4 Kg, 97%, 31.2 mol).After the solution was cooled to −5° C., vinyl Grignard (20.6 L, 1.6 Min THF, 32.8 mol) was added dropwise over a period of 1.5 h whilemaintaining the temperature below 0° C. The reaction was stirred for anadditional 60 min at −5 to 0° C., at which point HPLC assay indicated˜0.4 area % of starting material vs. product. Methyl chloroformate (2,2.74 L, d=1.223, 35.4 mol) was added via an addition funnel over 30 minwhile maintaining the temperature below 0° C. After stirring for 60 min,0.5 N HCl (40 L) was added, while maintaining the temperature <20° C.The organic layer was separated, and filtered through silica gel (4 Kg).The filtrates containing the product was concentrated to removesolvents. The weight of the concentrated material was 8.88 Kg. ¹H NMR ofthe solution showed the material was 56.7 wt %, yielding 5.01 Kg ofallyl carbonate 3 as a light yellow oil.

[2080]¹H-NMR(400 MHz, CDCl₃) δ 7.34 (q, 1H), 7.16 (d, 1H), 7.09 (d, 1H),7.02 (m, 1H), 6.02 (m, 2H), 5.36 (m, 2H), 3.85 (s, 3H).

[2081]¹³C-NMR (400 MHz, CDCl₃) δ 164.1, 161.6, 154.9, 140.8, 135.2,103.2, 122.5, 118.1. 114.6 (dd), 79.3, 54.9.

[2082] A 100 L round bottom flask was charged with dimethyl malonate(4a, 4.25 kg, 31.52 mol) and toluene (50 L), and was then flushed withnitrogen followed by the addition of sodium hydride (60% dispersion inmineral oil, 1.197 Kg, 29.94 mol) in roughly four equal portions over 20min. The resulting mixture was heated at 70° C. for 45 min and thencooled to 5° C. The thick slurry was filtered and flushed with heptaneto give the product 4b as a white fluffy solid (6.063 Kg, 81% pure,remainder toluene, quantitative yield).

[2083] A 22 L flask was charged with 1,1′-carbonyldiimidazole (1.7 Kg,10.48 mol) and THF (7.5 L). Solid picolinic acid (1.36 Kg, 11 mol) wasadded to the slurry at room temperature. The reaction was endothermiccausing the mixture to cool from 18° C. to 12° C. The reaction mixturewas then warmed to 18-19° C. The resulting clear solution was stirredfor 1 h and molten (1S,2S)-(+)-1,2-diaminocyclohexane (0.5 Kg, 4.38 mol)was added while keeping the temperature below 50° C. The beaker andfunnel were rinsed with 2.5 L of THF. The reaction was stirred at rt for15 h. Water (0.5 L) was added to the thin slurry giving a clear solutionand the reaction mixture was stirred for 1 h. The reaction mixture wasconcentrated to an orange semi-solid by rotary evaporation. The reactionproduct was slurried in 5 L of ethanol and concentrated by rotaryevaporation. The reaction product was dissolved in ethanol (5 L) at64-65° C. The solution was allowed to cool. The solution turned hazyaround 58° C. At this temperature, the hazy solution was seeded (10 g)and cooled to −8° C. The resulting white crystals were isolated byfiltration on a sintered glass funnel, washed with 5 L of cold ethanol(−8 to −10° C.), dried under house vacuum with nitrogen sweep, and thendried in a vacuum oven (35° C.). This resulted in the isolation of 1.23Kg (86.3%) of white crystalline solid.

[2084]¹H NMR (400 MHz, CDCl₃) δ 8.50-8.49 (m, 2H), 8.23 (d, J=6.47 Hz,2H), 8.02-7.99 (m, 2H), 7.69-7.64 (m, 2H), 7.29-7.24 (m, 2H), 4.03 (bs,2H), 2.18-2.15 (m, 2H), 1.79 (bs, 2H), 1.42-1.41 (m, 4H).

[2085]¹³C NMR (CDCl₃) δ 164.5, 149.8, 148.1, 136.9, 125.8, 122.0, 53.2,32.6, 24.8

[2086] A 2 L round bottom flask equipped with a mechanical stirrer,vacuum inlet, argon inlet and a septa was charged with MO(CO)₆ (218.8 g,0.828 mol; 0.1 eq.) and (1S,2S)-N,N′-dipicolinoyl-1,2-diaminocyclohexane(402 g, 1.242 mol; 0.15 eq.), and then evacuated and back filled withargon (3 cycles). To this mixture was added toluene (4.36 L) and theresulting solution was evacuated and back filled with argon (3 cycles).The solution was heated to 85° C. for 4.0 h. Separately, a 50 L flaskwas charged with sodium dimethyl malonate 4b (2.36 kg; 1.5 eq) andtoluene (30.6 L). The heterogeneous solution was heated to 50-55° C.followed by the addition of the carbonate 3 (87.1%; 2 kg; 8.28 mol; 1eq.) in toluene (3 L) and the molybdenum/ligand solution. The mixturewas heated at 85° C. for 15 h, and then cooled to 25-30° C. Water (20 L)was added to the mixture, and the resulting mixture was transferred toan extractor. The organic layer was separated, concentrated toapproximately 5 L, filtered through SiO₂, concentrated under vacuum, toafford an oil containing 2.077 Kg (94.3% yield, ee=96.1%) of the desiredproduct. Ratio of regioisomers was 19:1 trans to cis.

[2087]¹H-NMR (400 MHz, CDCl₃) δ 7.28 (m, 1H), 7.02 (d, 1H, J=7.8 Hz),6.95(m, 2H), 6.71 (m, 1H), 5.14 (dd, 2H), 4.12 (t, 1H, J=8.3 Hz)), 3.85(d, 1H, J=1.0 Hz), 3.76 (s, 3H), 3.54 (s, 3H).

[2088]¹³C-NMR (400 MHz, CDCl₃) δ 167.9, 167.6, 164.0, 161.6, 142.6,137.1, 130.1, 123.6, 117.2, 114.9(d), 114.1 (d), 57.1, 52.6, 49.3

[2089] A solution of dimethyl2-(1-(R)-(3-fluorophenyl)prop-2-en-1-yl)malonate e 5 (2.256 kg, 8.47mol; 36.1% by wt in MTBE, total wt 6.251 kg) was charged to a 50 L,4-necked round bottom flask, equipped with mechanical stirrer, stopper,thermocouple, and batch concentrator. The solution was concentrated at29″ vacuum until no more distillate was obtained at an internaltemperature of 15° C. To the orange oil was added water (11 L) and 5 NNaOH (5 L), and the resulting mixture was refluxed for 30 min. Themixture was allowed to cool to 18-23° C. and the volatiles were removedby distillation at atmospheric pressure. The distillation was stoppedwhen the level of methanol reached 3 mole percent. A total of 6.7 L ofdistillate was collected. The pH of the aqueous phase was adjusted to0.81 using conc. HCl (1.9 L). The mixture was refluxed for 12 h. Thereaction mixture was cooled to 46° C. and extracted twice with toluene(once with 5.5 L and once with 3.5 L). The toluene extracts werecombined and extracted once with 5% sodium chloride (aq) (3 L). Thetoluene solution was dried with sodium sulfate (1 kg) and filtered. Thesolution was assayed by HPLC. The yield was 1.429 kg (86.9%).

[2090]¹H NMR (CDCl₃) δ 2.77 (m, 2H), 3.87 (m, 1H), 5.12 (m, 2H), 5.96(m, 1H), 6.93 (m, 2H), 7.01 (m, 1H), 7.28

[2091] A 72 L, 4-necked flask, equipped with mechanical stirrer,thermocouple, reflux condenser with nitrogen inlet, addition funnel, andsteam pot, was charged with a toluene solution of the monoacid 6 (10.6kg of solution, 1.3 kg of monoacid, 6.69 mol). To the solution was addedacetonitrile (29.3 L), and the resulting mixture was heated to reflux.When the solution began to reflux (about 78° C.),(S)-α-methylbenzylamine (779 g) was added over 5 min. The solution wasallowed to cool. At 64° C., the salt began to crystallize. At 58° C.,ice bath cooling was applied. The temperature dropped to 10° C., and themixture was stirred at that temperature for 45 min. The mixture wasfiltered, and the cake was washed with an ice-cold 3:1 mixture ofacetonitrile and toluene (9 L). The monoacid salt wet cake was placedunder positive nitrogen pressure using a plastic bag over the filterpot.

[2092] A 50 L extractor was charged with the monoacid salt wet cake(13.91 moles). To the extractor were added water (20 L), 50% NaOH (820mL), and methylene chloride (12 L). The contents were mixed thoroughly,allowed to settle, and the layers were separated. The aqueous phase wasextracted again with methylene chloride (12 L). To the aqueous phase wasadded toluene (19 L) and conc. HCl (1.5 L). The layers were separated,and the aqueous phase was extracted again with toluene (4 L). Thetoluene extracts were combined and extracted with 5% sodium chloridesolution (10 L). The toluene layer was dried with sodium sulfate (1 kg).The mixture was filtered, the cake was washed with toluene (2 L), andthe combined filtrate and wash was assayed by HPLC. The yield was 2522 g(93.4% overall for salt formation and salt break).

[2093] The toluene solution of (3S)-3-(3-fluorophenyl)pent-4-enoic acidfrom Step E (11,230 g of a solution containing 1158 g of acid and 1043 gof a second solution containing 102 g of acid) was concentrated to anoil using a Buchi rotary evaporator. The oil was dissolved in methylenechloride (0.5 L). The KF was 36 μg/mL. A 50 L, 4-necked round bottomflask, equipped with mechanical stirrer, thermocouple, reflux condenserwith nitrogen inlet, addition funnel, and steam pot, was chargedsequentially with methylene chloride (5.5 L), monomethylmalonatepotassium salt (7, 1.52 kg), and magnesium chloride (618 g). The mixturewas cooled to 0-5° C. Triethylamine (2.71 L) was charged to the additionfunnel and added to the mixture over 2-5 min. The addition was slightlyexothermic; the temperature rose 2° C. The mixture was aged for 30 minat 0-5° C., then warmed to 20° C. and aged for 30 min. A 22 L, 4-neckedround bottom flask, equipped with mechanical stirrer, thermocouple,nitrogen inlet, dry ice condenser, and addition funnel, was charged withmethylene chloride (4 L) and 1,1′-carbonyldiimidazole (1.10 kg). Themonoacid solution from above was charged to the addition funnel andadded to the 22 L flask over 30-40 min to give a solution. Gas (CO₂)vigorously evolved, which entrained methylene chloride, hence the needfor the dry ice condenser. The resulting solution of activated monoacidwas pumped into the 50 L flask. The dry ice condenser was moved from the22 L flask to the top of the water condenser on the 50 L flask. Thereaction mixture was heated to 41° C. During the addition of activatedmonoacid, the temperature rose from 20.1° C. to 20.7° C. The temperaturecontinued to slowly rise to 28° C., at which point steam wasintermittently applied to the 50 L flask. The progress of the reactionwas followed by HPLC. When the reaction was complete (about 1.5 h), themixture was cooled to 0-5° C. To the cold mixture was added cold 2 N HCl(19 L). The pH of the aqueous phase was 2.9. The addition wasexothermic; the temperature increased to 20° C. The two phase mixturewas transferred to a 50 L extractor, and the layers were separated. Theaqueous phase was extracted with methylene chloride (3 L). The methylenechloride extracts were combined and dried with anhydrous sodium sulfate(1 kg). The mixture was filtered and the cake was washed with methylenechloride (1 L). The filtrate and washes were combined. Final yield was>95%.

[2094]¹H NMR (CD₃Cl) δ 2.98 (m, 2H), 3.39 (d, J=1.2 Hz, 2H), 3.70 (s,3H), 3.94 (m, 1H), 5.06 (m, 2H), 5.93, (m, 1H), 6.90 (m, 1H), 6.92 (m,1H), 6.99 (m, 1H), 7.26 (m, 1H).

[2095]¹³C NMR (CD₃Cl) δ 43.6, 47.8, 49.3, 52.2, 113.5 (d, J=20.9 Hz),114.4 (d, J=21.7 Hz), 115.3, 123.3 (d, J=3.2 Hz), 130.0 (d, J=8.0 Hz),139.5, 145.0 (d, J=7.2 Hz), 162.8 (d, J=Hz), 167.2, 200.2.

[2096] A 50 L, 4-necked round bottom flask, equipped with mechanicalstirrer, thermocouple, addition funnel, nitrogen inlet, and steam pot,was charged with a solution of methyl(5S)-5-(3-fluorophenyl)-3-oxohept-6-enoate 8 (8823 g of solution, 1300 gof ketoester in 1,2-dichloroethane). Additional 1,2-dichloroethane (7 L)was charged to the flask, followed by 4-acetamidobenzenesulfonyl azide(1.25 kg). The solution was heated from about 18° C. to 21° C. withsteam. (Note: the dissolution of azide was endothermic.) Triethylamine(2.17 L) was added over 40 min with water bath cooling to maintain atemperature of 19-23° C. The reaction was stirred at 18-23° C. forapproximately 9 h. The reaction was mildly exothermic. The reagentproduct, 4-acetamidobenzenesulfonyl amide, began to precipitate from thereaction during the addition of triethylamine and eventually formed athick slurry. The reaction was followed by HPLC and was judged completewhen the amount of starting material was <0.5%. When completed, thereaction mixture was filtered, and the cake was washed four times with1,2-dichloroethane (3×2 L displacement washes, 1×1 L slurry wash). Thefiltrate and washes were combined and extracted with cold (5-10° C.) 2NHCl (7.4 L). The extraction was exothermic and was done in a 50 Lextractor with cooling to maintain a temperature of 20-22° C. The pH ofthe aqueous phase was 1.0. The organic layer was extracted twice withwater (2×7 L). The organic extract was charged to a 50 L, 4-necked roundbottom flask, equipped with mechanical stirrer, thermocouple, nitrogeninlet, and stopper. The solution was dried for 4 h with sodium sulfate(1 kg). The organic solution was passed through a 5 μ inline filter. Thefinal weight of organic solution was 25.6 kg. Final yield of 9 was >95%.

[2097]¹H NMR (CDCl₃) δ 3.32 (d, J=7.6 Hz, 2H), 3.84 (s, 3H), 4.02 (m,1H), 5.08 (m, 2H), 5.97 (m, 1H), 6.90 (m, 1H), 6.96 (m, 1H), 7.04 (m,1H), 7.26 (m, 1H).

[2098] A 100 L flask equipped with a 5 L addition funnel, refluxcondenser, temperature probe, stopper, and air-driven overhead stirrerwas charged with 1,2-dichloroethane (11 L) and (CH₃CN)₄CuPF₆ (55.41 g,0.149 mol). The temperature-controlled water bath was set to 77° C., andthe starting methyl (5S)-5-(3-fluorophenyl)-2-diazo-3-oxohept-6-enoate 9(1373 g in DCE solution, 4.97 mol) was added to the reaction vessel overa period of 8 h, with the reaction temperature maintaining at 77-81° C.After finishing addition, reaction was stirred for 1 additional h, steamwas turned off, and ice was added to the water bath. After cooling for 2h the flask contents were pumped into a 100 L extractor, and thereaction flask was rinsed with 2 L methylene chloride. Brine (30 L) waspumped into the extractor and the mixture stirred for 10 min, thensettled for 30 min. The layers were separated and the organic layerswere dried over magnesium sulfate in a cold room overnight. The mixturewas filtered and the organic layers were concentrated, yielding 96.5% ofthe trans and cis mixture 10 and 10′, 77.5% of trans only (4.47:1trans:cis).

[2099]¹H-NMR (400 MHz, CDCl₃) δ 7.31 (m, 2H), 6.95 (m, 2H), 3.82 (s,3H), 3.49 (d, 1H, J=8.5 Hz), 2.76 (m, 1H), 2.64(dd, 1H, J=8.2 Hz), 2.28(d, 1H, J=19.1 Hz), 2.15 (m, 1H), 1.54 (t, 1H, J=5.3 Hz).

[2100]¹³C-NMR (400 MHz, CDCl₃) δ 205.4, 168.3, 163.1 (d, J=2.4 Hz),147.1, 130.8, 122.0, 114.1(d), 113.6(d), 52.6, 42.4, 39.1,39.0, 38.0,21.5.

[2101] A 72 L round bottom flask equipped with a temperature probe,overhead stirrer, nitrogen and vacuum inlet was charged with the mixtureof(1S,5R)-4-(S)-(3-fluorophenyl)-1-methoxycarbonyl-2-oxo[3.1.0]bicyclohexane(10) and(1R,5S)-4-(S)-(3-fluorophenyl)-1-methoxycarbonyl-2-oxo[3.1.0]bicyclohexane(10′) (6.45 Kg of 10 starting material, 3.4 mol) from Step G, sodiumacetate (2.77 Kg, 33.8 mol), and acetic acid (14 L, 244 mol). Themixture was evacuated and back filled with nitrogen (3 cycles) andheated to 105° C. for 15 h followed by distillation of 12-13 L of aceticacid. The mixture is cooled to 50° C. followed by the addition of DMF(15 L). To the solution was added 3N NaOH until pH=>12 (keeping solutiontemp <35° C.) followed by heating to 70° C. for 30 min. The solution wascooled to room temperature and transferred into an extractor. To theextractor was added 30 L of MTBE, and the aqueous layer separated andback extracted with 30 L of MTBE. The organic layers were combined,washed with 30 L of 10% sodium chloride in water, dried over magnesiumsulfate, filtered, and concentrated to yield 2.23 Kg of materialcontaining 698 g of product 12 (98% yield based on 10) with theremainder MTBE. This material was identical that that made in Example65, Step D.

[2102]¹H NMR (CDCl₃) δ 2.3-2.45 (m, 2H), 2.5 (m, 1H), 2.61 and 2.77(dABq, 2H), 2,28 (ddd, IH), 3.61 and 3.75 (dABq, 2H), 6.9-7.0 (m, 2H),7.06 (d, 1H), 7.3-7.4 (m, 1H).

[2103] Step I:N-Methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)-D-valine

[2104] Using essentially the same procedures as described in Example 65,Steps E-I, (+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanonefrom Step I was converted to the title compound. The free amine in thefinal step can be crystallized from ethanol or other appropriatesolvents to afford the crystalline free amine title compound rather thanthe salt.

EXAMPLE 105

[2105] Using essentially the same procedures as in Examples 35 or 65,but substituting the appropriate L- and/or D-amino-acid t-butyl ester,with or without a subsequent alkylation with formaldehyde oracetaldehyde, and employing one of the appropriate piperidines as listedin Procedures 1-46, a variety of other final compounds can also preparedbesides those described in the above Examples.

[2106] While the invention has been described and illustrated withreference to certain particular embodiments thereof, those skilled inthe art will appreciate that various adaptations, changes,modifications, substitutions, deletions, or additions of procedures andprotocols may be made without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A compound of the formula I:

wherein: X is selected from: —(C₀₋₆ alkyl)—Y—(C₀₋₆ alkyl)—, —(C₀₋₆alkyl)—C₃₋₈ cycloalkyl-(C₀₋₆ alkyl)—, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl,where the alkyl is unsubstituted or substituted with 1-7 substituentswhere the substituents are independently selected from: (a) halo, (b)hydroxy, (c) —O—C₁₋₃ alkyl, and (d) trifluoromethyl, and where Y isselected from: a single bond, —O—, —SO₂—, —NR¹⁰—, —NR¹⁰—SO₂—,—SO₂—NR¹⁰—, —S—, and —SO—, and where R¹⁰ is independently selected from:hydrogen, C₁₋₆ alkyl, benzyl, phenyl, and C₁₋₆ alkyl-C₃₋₆ cycloalkyl,which is unsubstituted or substituted with 1-3 substituents where thesubstituents are independently selected from: halo, C₁₋₃ alkyl, C₁₋₃alkoxy and trifluoromethyl; R¹ is selected from: (1) —CO₂H, (2) —NO₂,(3) -tetrazolyl, (4) -hydroxyisoxazole, (5) —SO₂NHCO—(C₀₋₃ alkyl)-R⁹,wherein R⁹ is independently selected from: hydrogen, C₁₋₆ alkyl, C₅₋₆cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with1-3 substituents where the substituents are independently selected from:halo, C₁₋₃ alkyl, C₁₋₃ alkoxy and trifluoromethyl, and (6)—-P(O)(OH)₂;R³ is selected from the group consisting of: phenyl and heterocycle,which is unsubstituted or substituted with 1-7 substituents where thesubstituents are independently selected from: (a) halo, (b)trifluoromethyl, (c) hydroxy, (d) C₁₋₃ alkyl, (e) —O—C₁₋₃ alkyl, (f)—CO₂R⁹, (g) —NR⁹R¹⁰, and (h) —CONR⁹R¹⁰; R⁴, R⁵ and R⁶ are independentlyselected from: hydrogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₃₋₁₀ alkenyl,C₂₋₁₀ alkynyl, phenyl, —(C₁₋₆ alkyl)-phenyl, —(C₁₋₆ alkyl)-C₃₋₈cycloalkyl, naphthyl, biphenyl, and heterocycle, which is unsubstitutedor substituted with 1-7 of R¹¹ where R¹¹ is independently selected from:(a) halo, (b) trifluoromethyl, (c) hydroxy, (d) C₁₋₃ alkyl, (e) —O—C₁₋₃alkyl, (f) —CO₂R⁹, (g) —NR⁹R¹⁰, and (h) —CONR⁹R¹⁰, or where R⁴ and R⁵may be joined together to form a 3-8 membered saturated ring which maybe unsubstituted or substituted with 1-7 of R¹¹, or where R⁵ and R⁶ maybe joined together to form a 3-8 membered saturated ring which may beunsubstituted or substituted with 1-7 of R¹¹; R⁷ is selected from: (1)hydrogen, (2) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-4substituents where the substituents are independently selected from:hydroxy, cyano, and halo, (3) hydroxy, and (4) halo; R⁸ is selectedfrom: hydrogen, C₃₋₈ cycloalkyl, phenyl, naphthyl, biphenyl, andheterocycle, which is unsubstituted or substituted with 1-7 of R¹² whereR¹² is independently selected from: (a) halo, (b) cyano, (c) hydroxy,(d) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5 of R¹³where R¹³ is independently selected from: halo, cyano, hydroxy, C₁₋₆alkoxy, —CO₂H, —CO₂(C₁₋₆ alkyl), trifluoromethyl, and —NR⁹R¹⁰, (e)—O—C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5 of R¹³,(f) —CF₃, (g) —CHF₂, (h) —CH₂F, (i) —NO₂, (j) C₀₋₆ alkyl-phenyl or C₀₋₆alkyl-heterocycle, which is unsubstituted or substituted with 1-7substituents where the substituents are independently selected from: (i)halo, (ii) hydroxy, (iii) C₁₋₆ alkyl, unsubstituted or substituted with1-5 substituents, each of which is independently selected from halo,cyano, hydroxy, C₁₋₆ alkoxy, —CO₂H, —CO₂(C₁₋₆ alkyl), trifluoromethyl,and —NR⁹R¹⁰, (iv) —O—C₁₋₆ alkyl, (v) —CF₃, (vi) —OCF₃, (vii) —NO₂,(viii) —CN, (ix) —SO₂—C₁₋₆ alkyl, (x) —CO₂R⁹, (xi) —NR⁹R¹⁰, (xii)—CONR⁹R¹⁰, (xiii) —SO₂—NR⁹R¹⁰, (xiv) —NR⁹—SO₂—R¹⁰, (xv) —C₃₋₈cycloalkyl, (xvi) —OC₃₋₈ cycloalkyl, and (xvii) phenyl; (k) —CO₂R⁹, (l)tetrazolyl, (m) —NR⁹R¹⁰, (n) —NR⁹—COR¹⁰, (o) —NR⁹—CO₂R¹⁰, (p)—CO—NR⁹R¹⁰, (q) —OCO—NR⁹R¹⁰, (r) —NR⁹CO—NR⁹R¹⁰, (s) —S(O)_(m)—R⁹,whereinm is an integer selected from 0, 1 and 2, (t) —S(O)2—NR⁹R¹⁰, (u)—NR⁹S(O)₂—R¹⁰, (v) —NR⁹S(O)₂—NR⁹R¹⁰, (w) C₁₋₆ alkyl substituted with—C₃₋₈ cycloalkyl, and (x) —C₃₋₈ cycloalkyl; n is an integer selectedfrom 1, 2, 3 and 4; x is an integer selected from 0, 1 and 2, and y isan integer selected from 0, 1 and 2, with the proviso that the sum of xand y is 2; and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.
 2. The compound of claim 1, wherein R¹ isselected from (1) —CO₂H, (2) —NO₂, (3) -tetrazolyl, (4)-hydroxyisoxazole, and (5) —P(O)(OH)₂; R⁸ is selected from: hydrogen,C₃₋₈ cycloalkyl, phenyl, naphthyl, biphenyl, and heterocycle, which isunsubstituted or substituted with 1-7 of R¹² where R¹² is independentlyselected from: (a) halo, (b) cyano, (c) hydroxy, (d) C₁₋₆ alkyl, whichis unsubstituted or substituted with 1-5 of R¹³ where R¹³ isindependently selected from: halo, cyano, hydroxy, C₁₋₆ alkoxy, —CO₂H,—CO₂(C₁₋₆ alkyl), trifluoromethyl, and —NR⁹R¹⁰, (e) —O—C₁₋₆ alkyl, whichis unsubstituted or substituted with 1-5 of R¹³, (f) —CF₃, (g) —CHF₂,(h) —CH₂F, (i) —NO₂, (j) C₀₋₆ alkyl-phenyl or C₀₋₆ alkyl-heterocycle,which is unsubstituted or substituted with 1-7 substituents where thesubstituents are independently selected from: (i) halo, (ii) hydroxy,(iii) C₁₋₆ alkyl, (iv) —O—C₁₋₆ alkyl, (v) —CF₃, (vi) —OCF₃, (vii) —NO₂,(viii) —CN, (ix) —SO₂—C₁₋₆ alkyl, (x) —CO₂R⁹, (xi) —NR⁹R¹⁰, (xii)—CONR⁹R¹⁰, (xiii) —SO₂—NR⁹R¹⁰, and (xiv) —NR⁹—SO₂—R¹⁰; (k) —CO₂R⁹, (l)tetrazolyl, (m) —NR⁹R¹⁰, (n) —NR⁹—COR¹⁰, (o) —NR⁹—CO₂R¹⁰, (p)—CO—NR⁹R¹⁰, (q) —OCO—NR⁹R¹⁰, (r) —NR⁹CO—NR⁹R¹⁰, (s) —S(O)_(m)—R⁹,whereinm is an integer selected from 0, 1 and 2, (t) —S(O)₂—NR⁹R¹⁰, (u)—NR⁹S(O)₂—R¹⁰, and (v) —NR⁹S(0)2—NR⁹R¹⁰; and pharmaceutically acceptablesalts thereof and individual diastereomers thereof.
 3. The compound ofclaim 1 wherein R¹ is selected from: (1) —CO₂H, and (2) -tetrazolyl. 4.The compound of claim 1 wherein R¹ is —CO₂H.
 5. The compound of claim 1wherein R³ is selected from the group consisting of: phenyl and thienyl,which may be unsubstituted or substituted with 1-5 substituents wherethe substituents are independently selected from: (a) halo, (b)trifluoromethyl, (c) hydroxy, (d) C₁₋₃ alkyl, and (e) —O—C₁₋₃ alkyl. 6.The compound of claim 1 wherein R³ is selected from the group consistingof: phenyl and thienyl, which may be unsubstituted or substituted with1-5 substituents where the substituents are independently selected from:(a) fluoro, (b) chloro, (c) trifluoromethyl, (d) hydroxy, and (e) C₁₋₃alkyl.
 7. The compound of claim 1 wherein R³ is selected from the groupconsisting of: phenyl, which may be unsubstituted or substituted with1-5 substituents where the substituents are independently selected from:(a) fluoro, and (b) chloro; and unsubstituted thienyl.
 8. The compoundof claim 1 wherein R³ is unsubstituted phenyl, (3-fluoro)phenyl or3-thienyl.
 9. The compound of claim 1 wherein R⁴ is hydrogen.
 10. Thecompound of claim 1 wherein R⁵ is selected from: hydrogen, C₁₋₆ alkyl,C₃₋₈ cycloalkyl, C₁₋₆ alkyl-C₃₋₈ cycloalkyl, and phenyl.
 11. Thecompound of claim 1 wherein R⁵ is selected from: hydrogen, methyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,—CH₂-cyclopropyl, —CH₂-cyclobutyl, and phenyl.
 12. The compound of claim1 wherein R⁵ is selected from: isopropyl, isobutyl, sec-butyl, andcyclohexyl.
 13. The compound of claim 1 wherein R⁶ is selected from:hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyl-C₃₋₈ cycloalkyl, andphenyl.
 14. The compound of claim 1 wherein R⁶ is selected from:hydrogen, methyl, n-butyl, t-butyl, isobutyl, sec-butyl,—CH₂-cyclopropyl, —CH₂— cyclobutyl, and cyclohexyl.
 15. The compound ofclaim 1 wherein R⁶ is selected from: hydrogen, methyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, and cyclohexyl.
 16. The compound of claim 1 wherein R⁷is hydrogen, fluoro, hydroxy or C₁₋₆ alkyl.
 17. The compound of claim 1wherein R⁷ is hydrogen.
 18. The compound of claim 1 wherein X is: —(C₀₋₄alkyl)—Y—(C₀₋₄ alkyl)—, where the alkyl is unsubstituted or substitutedwith 1-4 substituents where the substituents are independently selectedfrom: (a) halo, (b) hydroxy, (c) —O—C₁₋₃ alkyl, and (d) trifluoromethyl,and where Y is selected from: a single bond, —O—, —SO₂—, —NR¹⁰—, —S—,and —SO—, and where R¹⁰ is independently selected from: hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, benzyl, phenyl, and C₁₋₆ alkyl-C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-3 substituentswhere the substituents are independently selected from: halo, C₁₋₃alkyl, C₁₋₃ alkoxy and trifluoromethyl.
 19. The compound of claim 1wherein X is: —(C₀₋₂ alkyl)—Y—(C₀₋₂ alkyl)—, where the alkyl isunsubstituted or substituted with 1-4 substituents where thesubstituents are independently selected from: (a) halo, (b) hydroxy, (c)—O—C₁₋₃ alkyl, and (d) trifluoromethyl, and where Y is selected from: asingle bond, —O—, —SO₂—, —NR¹⁰—, —S—, and —SO—, where R¹⁰ isindependently selected from: hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, benzyl, phenyl, and C₁₋₆ alkyl-C₃₋₆ cycloalkyl, which isunsubstituted or substituted with 1-3 substituents where thesubstituents are independentlyselected from: halo, C₁₋₃ alkyl, C₁₋₃alkoxy and trifluoromethyl.
 20. The compound of claim 1 wherein X isselected from: —(C₀₋₂ alkyl)—Y—(C₀₋₂ alkyl)—, where the alkyl isunsubstituted or substituted with fluoro, and where Y is selected from:a single bond, —SO₂—, —SO—, and —NR¹⁰—, where R¹⁰ is independentlyselected from: hydrogen, C₁₋₃ alkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. 21.The compound of claim 1 wherein X is selected from: (1) a single bond,(2) —CH₂CH₂—, (3) —CH₂CH₂CH₂—, (4) —CH₂CH₂—CF2—, (5) —CH₂CH₂—SO₂—, and(6) —CH₂CH₂—SO—.
 22. The compound of claim 1 wherein R⁸ is selectedfrom: phenyl, naphthyl, cyclohexyl, benzoimidazolyl, benzofurazanyl,imidazopyridyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl,pyridazinyl, pyridyl, pyrimidyl, thiazolyl, tetrazolopyridyl, andpyrazolyl; which is unsubstituted or substituted with 1-7 substituentswhere the substituents are independently selected from: (a) halo, (b)cyano, (c) hydroxy, (d) C₁₋₆ alkyl, which is unsubstituted orsubstituted with 1-5 of R¹³ where R¹³ is independently selected from:halo, cyano, hydroxy, C₁₋₆ alkoxy, —CO₂H, —CO₂(C₁₋₆ alkyl),trifluoromethyl, and —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independentlyselected from: hydrogen, C₁₋₆ alkyl, C₅₋₆ cycloalkyl, benzyl or phenyl,which is unsubstituted or substituted with 1-3 substituents where thesubstituents are independently selected from: halo, C₁₋₃ alkyl, C₁₋₃alkoxy and trifluoromethyl; (e) —O—C₁₋₆ alkyl, which is unsubstituted orsubstituted with 1-5 of R¹³, (f) —CF₃, (g) —CEF₂, (h) —CH₂F, (i) —NO₂,(j) C₀₋₆ alkyl-phenyl or C₀₋₆ alkyl-heterocycle, which is unsubstitutedor substituted with 1-7 substituents where the substituents areindependently selected from: (i) halo, (ii) hydroxy, (iii) C₁₋₆ alkyl,(iv) —O—C₁₋₆ alkyl, (v) —CF₃, (vi) —OCF₃, (vii) —NO₂, (viii) —CN, (ix)—SO₂—C₁₋₆ alkyl, (x) —CO₂R⁹, (xi) —NR⁹R¹⁰, (xii) —CONR⁹R¹⁰, (xiii)—SO2—NR⁹R¹⁰, and (xiv) —NR⁹—SO₂—R¹⁰; (k) —CO2R⁹, (l) tetrazolyl, (m)—NR⁹R¹⁰, (n) —NR⁹—COR¹⁰, (o) —NR⁹—CO₂R¹⁰, (p) —CO—NR⁹R¹⁰, (q)—OCO—NR⁹R¹⁰, (r) —NR⁹CO—NR⁹R¹⁰, (s) —S(O)_(m)—R⁹,wherein m is an integerselected from 0, 1 and 2, (t) —S(O)₂—NR⁹R¹⁰, (u) —NR⁹S(O)₂—R¹⁰, and (v)—NR⁹S(O)₂—NR⁹R¹⁰.
 23. The compound of claim 1 wherein R⁸ is selectedfrom: phenyl, imidazopyridyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl,and thiazolyl; which is unsubstituted or substituted with 1-5substituents where the substituents are independently selected from: (a)halo, (b) cyano, (c) —NO₂, (d) —CF₃, (e) —CHF₂, (f) —CH₂F, (h) C₁₋₆alkyl, (i) C₁₋₃ alkyl-phenyl or C₁₋₃ alkyl-pyridyl, which isunsubstituted or substituted with 1-4 substituents where thesubstituents are independently selected from: (i) halo, (ii) C_(I-)6alkyl, (iii) —O—C₁₋₆ alkyl, (iv) —CF₁₋₃, (vi) —OCF₃, (vii) —CN, and (j)—O—C₁₋₆ alkyl.
 24. The compound of claim 1 wherein R⁸ is selected from:imidazolyl, oxazolyl, pyrazolyl, and thiazolyl; which is unsubstitutedor substituted with 1-3 substituents where the substituents areindependently selected from: (a) fluoro, (b) cyano, (c) C₁₋₃ alkyl, (d)—CH₂-phenyl, which is unsubstituted or substituted with 1-4 substituentswhere the substituents are independently selected from: (i) fluoro, (ii)chloro, (iii) —O—CH₃, (iv) —CF₃, (v) —CN, and (e) —CF₃.
 25. The compoundof claim 1 wherein R⁸ is selected from: 5-(3-benzyl)pyrazolyl,5-(1-methyl-3-benzyl)pyrazolyl, 5-(1-ethyl-3-benzyl)pyrazolyl,5-(2-benzyl)thiazolyl, 5-(2-benzyl-4-methyl)thiazolyl, and5-(2-benzyl-4-ethyl)thiazolyl).
 26. The compound of claim 1 wherein n isan integer which is
 1. 27. The compound of claim 1 wherein x is aninteger which is 1 and y is an integer which is
 1. 28. The compound ofclaim 1, which is a compound of formula (II):

wherein

R⁸ is selected from the group consisting of

R¹² and R¹⁴ are each independently selected from the group consisting ofF, Cl, CF₃, OCH₃, OCH₂CH₃, OCF₃, O-cyclobutyl, CN, O-cyclopropyl, CH₃,CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, and SO₂CH₃; G is hydrogen or fluoro; and q isan integer equal to 1 or 2; and pharmaceutically acceptable saltsthereof and individual diastereomers thereof.
 29. The compound of claim1, which is a compound selected from the group consisting of

and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.
 30. The compound of claim 1, which is a compoundselected from the group consisting of

and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.
 31. The compound of claim 1, which is a compoundselected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 32. The compound of claim31, which is

or a pharmaceutically acceptable salt thereof.
 33. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1.34. The pharmaceutical composition of claim 33, wherein the compound ofclaim 1 is a compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 35. The pharmaceuticalcomposition of claim 34, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 36. A method formodulation of chemokine receptor activity in a mammal which comprisesthe administration of an effective amount of the compound of claim 1.37. A method for preventing infection by HIV, treating infection by HIV,delaying of the onset of AIDS, or treating AIDS comprising theadministration to a patient of an effective amount of the compound ofclaim
 1. 38. A method for the prevention or treatment of an inflammatoryand immunoregulatory disorder or disease which comprises theadministration to a patient of an effective amount of the compound ofclaim
 1. 39. A method for the prevention or treatment of asthma,allergic rhinitis, dermatitis, conjunctivitis, atherosclerosis orrheumatoid arthritis which comprises the administration to a patient ofan effective amount of the compound of claim 1.